A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma

Melanoma Clinical Trial

— COMBI-i  

Official title:

A Randomized, Double-blind, Placebo-controlled, Phase III Study Comparing the Combination of PDR001, Dabrafenib and Trametinib Versus Placebo, Dabrafenib and Trametinib in Previously Untreated Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02967692
• Other study ID #: CPDR001F2301
• Secondary ID: 2016-002794-35
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: February 17, 2017
• Est. completion date: August 26, 2024

Study information

• Verified date: June 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To evaluate the safety and efficacy of the combination of an anti-PD-1 antibody (Spartalizumab (PDR001)), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in unresectable or metastatic BRAF V600 mutant melanoma

Description:

This study is designed as a Phase III, multi-center study consisting of three parts:

• Part 1, known as the Safety Run-in, is an open-label part aimed at determining the recommended Phase III regimen (RP3R) of spartalizumab in combination with dabrafenib and trametinib for previously untreated subjects with BRAF V600 mutant unresectable or metastatic melanoma (Stage IIIC/IV per AJCC edition 7). In Part 1, spartalizumab was administered at a starting dose level (DL1) of 400 mg every 4 weeks (Q4W), along with fixed doses of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily). The RP3R for Part 3 was determined using the Bayesian Logistic Regression Model (BLRM) with escalation with overdose control (EWOC) criteria.

• Part 2, referred to as the Biomarker Cohort, is an open-label section focused on characterizing the kinetics of immune biomarkers and potential immune resistance mechanisms. Part 2 started when the fourth subject in dose level 1 (DL1) of Part 1 completed approximately 4 weeks of study treatment, and fewer than 3 dose-limiting toxicities (DLTs) were observed. Participants in Part 2 receive PDR001 (spartalizumab) at a dosage of 400 mg Q4W, in combination with dabrafenib (150 mg BID) and trametinib (2 mg QD).

• Part 3 is a double-blind, randomized, placebo-controlled phase that compares the efficacy and safety of spartalizumab in combination with dabrafenib and trametinib to placebo in combination with dabrafenib and trametinib. Part 3 was initiated after determining the RP3R for the combination of spartalizumab with dabrafenib and trametinib in Part 1. Subjects were randomized in a 1:1 ratio to receive either the RP3R dose of spartalizumab identified in Part 1 or placebo, along with dabrafenib (150 mg BID) and trametinib (2 mg QD).

For all parts of the study, the treatment is continued until the subject experiences any of the following events: disease progression according to RECIST 1.1 as determined by the Investigator, unacceptable toxicity, initiation of a new anti-neoplastic therapy, pregnancy, withdrawal of consent, physician's decision, loss to follow-up, death, or termination of the study by the Sponsor. Safety evaluations are conducted for all subjects for up to 150 days after the last dose of spartalizumab/placebo (safety follow-up period).

Subjects who discontinue study treatment without disease progression as per RECIST 1.1 continue with tumor assessments according to the protocol until documented disease progression, withdrawal of consent, loss to follow-up, or death, regardless of the initiation of new anti-neoplastic therapy (efficacy follow-up period).

Subjects enter the survival follow-up period after completing the safety follow-up period or experiencing disease progression as per RECIST 1.1 or response criteria for immunotherapy, whichever period is longer (survival follow-up period).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 569
• Est. completion date: August 26, 2024
• Est. primary completion date: August 11, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria Part 1: Safety run-in

• Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation

• Aspartate transaminase (AST) < 2.5× ULN and Alanine transaminase (ALT) < 2.5× ULN

• Measurable disease according to RECIST 1.1

• ECOG performance status = 1

Part 2: Biomarker cohort

• Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation

• At least two cutaneous or subcutaneous or nodal lesions for tumor sample collection

• Measurable disease according to RECIST 1.1

• ECOG performance status = 2

Part 3: Double-blind, randomized, placebo-controlled part

• Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation

• ECOG performance status = 2

• Measurable disease according to RECIST 1.1

Exclusion Criteria:

Part 1: Safety run-in

• Subjects with uveal or mucosal melanoma

• Any history of CNS metastases

• Prior systemic anti-cancer treatment for unresectable or metastatic melanoma

• Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior to enrollmen

• Radiation therapy within 4 weeks prior to start of study treatment

• Active autoimmune disease, and/or history of autoimmune disease(s) that required treatment

Parts 2 & 3: Biomarker cohort & double-blind, randomized, placebo-controlled part

• Subjects with uveal or mucosal melanoma

• Prior systemic anti-cancer treatment for unresectable or metastatic melanoma

• Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior to enrollment

• Radiation therapy within 4 weeks prior to start of study treatment

• Clinically active cerebral melanoma metastasis.

• Active autoimmune disease, and/or history of autoimmune disease(s) that required treatment

Other protocol-defined Inclusion/Exclusion may apply.

Related Conditions & MeSH terms

• Melanoma

Intervention

Biological:
• Spartalizumab
Spartalizumab powder for solution is used in Part 1 and Part 2, and as concentrate for solution for infusion for Part 3. Spartalizumab is administered via intravenous infusion over 30 minutes once every 4 weeks

Other:
• Placebo
Placebo is administered via intravenous infusion over 30 minutes once every 4 weeks

Drug:
• Dabrafenib
Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.
• Trametinib
Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Australia	Novartis Investigative Site	Gateshead	New South Wales
Australia	Novartis Investigative Site	Greenslopes	Queensland
Australia	Novartis Investigative Site	Nedlands	Western Australia
Australia	Novartis Investigative Site	North Sydney	New South Wales
Australia	Novartis Investigative Site	Prahran	Victoria
Austria	Novartis Investigative Site	Graz
Austria	Novartis Investigative Site	Innsbruck	Tyrol
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	St Poelten
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Jette	Brussel
Brazil	Novartis Investigative Site	Curitiba	PR
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Rio de Janeiro
Brazil	Novartis Investigative Site	Sao Paulo	SP
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Sofia
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Sherbrooke	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
Chile	Novartis Investigative Site	Santiago
Chile	Novartis Investigative Site	Santiago
Chile	Novartis Investigative Site	Temuco	Araucania
Czechia	Novartis Investigative Site	Brno
Czechia	Novartis Investigative Site	Hradec Kralove	CZE
Czechia	Novartis Investigative Site	Olomouc	CZE
Czechia	Novartis Investigative Site	Ostrava	Poruba
Czechia	Novartis Investigative Site	Praha
Czechia	Novartis Investigative Site	Praha 10
Czechia	Novartis Investigative Site	Zlin	Czech Republic
Denmark	Novartis Investigative Site	Aarhus
France	Novartis Investigative Site	Amiens
France	Novartis Investigative Site	Besancon Cedex
France	Novartis Investigative Site	Bobigny Cedex
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Boulogne Billancourt
France	Novartis Investigative Site	Caen
France	Novartis Investigative Site	Clermont Ferrand
France	Novartis Investigative Site	Dijon
France	Novartis Investigative Site	Grenoble
France	Novartis Investigative Site	Le Mans	Cedex 09
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Limoges	Haute Vienne
France	Novartis Investigative Site	Lorient
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Mulhouse cedex
France	Novartis Investigative Site	Nice
France	Novartis Investigative Site	Paris 10
France	Novartis Investigative Site	Pierre Benite
France	Novartis Investigative Site	Poitiers
France	Novartis Investigative Site	Reims
France	Novartis Investigative Site	Rouen Cedex
France	Novartis Investigative Site	Strasbourg Cedex
France	Novartis Investigative Site	Toulouse
France	Novartis Investigative Site	Vandoeuvre-les-Nancy
France	Novartis Investigative Site	Villejuif
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Chemnitz
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Erfurt
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Gera
Germany	Novartis Investigative Site	Halle Saale
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Homburg
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Mannheim	Baden Wuerttemberg
Germany	Novartis Investigative Site	Marburg
Germany	Novartis Investigative Site	Minden
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenster
Germany	Novartis Investigative Site	Regensburg	Bavaria
Germany	Novartis Investigative Site	Stade
Germany	Novartis Investigative Site	Tuebingen
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Szeged
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Ramat Gan
Italy	Novartis Investigative Site	Bari	BA
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Candiolo	TO
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Meldola	FC
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Padova	PD
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Siena	SI
Italy	Novartis Investigative Site	Torino	TO
Italy	Novartis Investigative Site	Verona	VR
Japan	Tokyo Metropolitan Komagome Hospital	Bunkyo ku	Tokyo
Japan	National Cancer Hospital	Chuo ku	Tokyo
Japan	Kyushu University Hospital	Fukuoka city	Fukuoka
Japan	Osaka International Cancer Institute	Osaka-city	Osaka
Japan	Kyoto University Hospital	Sakyo Ku	Kyoto
Mexico	Novartis Investigative Site	Guadalajara	Jalisco
Mexico	Novartis Investigative Site	Leon	Guanajuato
Mexico	Novartis Investigative Site	Mexico	Distrito Federal
Netherlands	Novartis Investigative Site	Breda
Netherlands	Novartis Investigative Site	Leiden
Norway	Novartis Investigative Site	Oslo
Poland	Novartis Investigative Site	Gdansk
Poland	Novartis Investigative Site	Warszawa
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Porto
Russian Federation	Novartis Investigative Site	Chelyabinsk
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Nizhny Novgorod
Russian Federation	Novartis Investigative Site	Omsk
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	Samara
Russian Federation	Novartis Investigative Site	St Petersburg
Spain	Novartis Investigative Site	Badalona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Jerez	Cadiz
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	Las Palmas de Gran Canaria
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Oviedo	Asturias
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Sweden	Novartis Investigative Site	Goteborg
Sweden	Novartis Investigative Site	Lund
Sweden	Novartis Investigative Site	Stockholm
Switzerland	Novartis Investigative Site	Aarau
Switzerland	Novartis Investigative Site	Zuerich
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Songkhla	Hat Yai
United Kingdom	Novartis Investigative Site	Leicester
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Middlesbrough
United Kingdom	Novartis Investigative Site	Northwood	Middlesex
United Kingdom	Novartis Investigative Site	Preston
United Kingdom	Novartis Investigative Site	Surrey	England
United Kingdom	Novartis Investigative Site	Sutton	Surrey
United Kingdom	Novartis Investigative Site	Truro	Cornwall
United States	California Cancer Associates for Research and Excellence SC-2	Encinitas	California
United States	Univ of TX MD Anderson Cancer Cntr SC 2	Houston	Texas
United States	University of Tennessee Medical Center SC	Knoxville	Tennessee
United States	Johns Hopkins U SC	Lutherville	Maryland
United States	NYU Laura and Isaac Perlmutter Cancer Center SC	New York	New York
United States	Nebraska Cancer Specialists	Omaha	Nebraska
United States	UC Irvine Medical Center SC	Orange	California
United States	University of Pittsburgh Med Center SC	Pittsburgh	Pennsylvania
United States	Utah Cancer Specialists SC 2	Salt Lake City	Utah
United States	California Pacific Medical Center	San Francisco	California
United States	Stanford Cancer Center SC-2	Stanford	California
United States	University of Kansas Cancer Center SC	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Canada,  Chile,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Japan,  Mexico,  Netherlands,  Norway,  Poland,  Portugal,  Russian Federation,  Spain,  Sweden,  Switzerland,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety Run-In (Part 1): Number of Participants With Dose Limiting Toxicities (DLTs)	DLT was defined as an adverse event or abnormal laboratory value that was unrelated to disease, disease progression, inter-current illness, or concomitant medications and occured within 8 weeks of treatment with spartalizumab in combination with dabrafenib and trametinib. The DLT criteria included Grade 4 hematological adverse events, Grade 4 bilirubin elevation, specific gastrointestinal adverse events, symptomatic serum amylase or lipase elevation, Grade 3 or higher hypertension, Grade 3 or higher cardiac events, Grade 2 or higher pneumonitis, Grade 3 or higher immune-related toxicities, infusion-related reactions, other clinically significant adverse events, and toxicities leading to a dosing delay of over 12 weeks. NCI CTCAE v4.03 was used for grading DLTs	Up to 8 weeks (Part 1)
Primary	Biomarker Cohort (Part 2): Change From Baseline in Programmed Cell Death-ligand 1 (PD-L1) Expression Upon Treatment With Spartalizumab in Combination With Dabrafenib and Trametinib	Change from baseline in PD-L1 expression (as determined by immunohistochemistry in tissue samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2	Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days
Primary	Biomarker Cohort (Part 2): Change From Baseline in CD8+ Cells Upon Treatment With Spartalizumab in Combination With Dabrafenib and Trametinib	Change from baseline in CD8+ cells (as determined by flow cytometry in blood samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2	Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days
Primary	Randomized (Part 3): Progression-Free Survival (PFS) as Per Investigator's Assessment by RECIST 1.1	Progression-free survival was defined as the time from the date of first dose to the date of the first documented radiological progression per investigator's assessment according to RECIST 1.1 or death due to any cause. The distribution of PFS was estimated using the Kaplan-Meier (KM) method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment.	Up to disease progression or death due to any cause, whichever occurs first, assessed up to 2.8 years (Part 3)
Secondary	Overall Survival (OS)	Overall survival is defined as the time from date of randomization to date of death due to any cause	Up to death due to any cause, assessed up to approximately 5 years
Secondary	Overall Response Rate (ORR) as Per Investigator's Assessment by RECIST 1.1	ORR was defined as the percentage of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1.; CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters	Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 years
Secondary	Duration of Response (DOR) as Per Investigator's Assessment by RECIST 1.1	DOR was defined as the time from first documented response of CR or PR to date of first documented progression or death, according to RECIST 1.1 criteria. The distribution of DOR was estimated using the KM method.; CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters	From first documented response to date of first documented progression or death, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3)
Secondary	Disease Control Rate (DCR) as Per Investigator's Assessment by RECIST 1.1	DCR was defined as the percentage of participants with CR or PR or subjects with stable disease (SD) lasting for a duration of at least 24 weeks as per local review according to RECIST 1.1 criteria.; CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.	Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 year
Secondary	Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status Scores	The EORTC QLQ-C30 was a 30-item questionnaire that patients complete, consisting of both multi-item scales and single-item measures. It included five functional scales, three symptom scales, six single items, and a Global Health Status/Quality of Life (GHS/QoL) scale.; The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life.; The change from baseline in GHS/QoL scores was calculated. A positive change from baseline indicated improvement in the patient's quality of life.	From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
Secondary	Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Physical Functioning Scale Scores	The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale.; The EORTC QLQ-C30 physical functioning scale measured a patient's ability to carry out daily activities and tasks requiring physical exertion. It consisted of five questions asking patients to rate their level of physical functioning, with response options ranging from 1="not at all" to 4="very much". The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating better physical functioning.; The change from baseline in physical functioning scale scores was calculated. A positive change from baseline indicated improvement in physical functioning.	From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
Secondary	Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Pain Symptom Scale Scores	The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale.; The EORTC QLQ-C30 pain symptom scale was one of the symptom scales in the questionnaire, which measured the severity of pain experienced by the patient. The pain symptom scale consisted of two items, one measuring the severity of pain and the other measuring the use of painkillers. The items were rated on a 4-point scale ranging from 1="not at all" to 4="very much". The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating more severe pain.; The change from baseline in pain symptom scale scores was calculated. A negative change from baseline indicated improvement.	From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
Secondary	Randomized (Part 3): Time to 10 Point Definitive Deterioration in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status	The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale.; The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life.; The time to definitive 10 point deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the GHS/QoL score or death due to any cause. If a subject had not had an event, the time to deterioration was censored at the date of the last adequate assessment. The distribution was estimated using KM method.	From baseline to date of at least 10 points relative to baseline worsening of the global health status score or death due to any cause, up to 2.8 years (Part 3)
Secondary	Randomized (Part 3): Change From Baseline in Function Assessment Cancer Therapy-melanoma (FACT-M) Melanoma Subscale Score	The Functional Assessment of Cancer Therapy-Melanoma (FACT-M) quality of life questionnaire was composed of the FACT-General (FACT-G) plus the Melanoma Subscale and the Melanoma Surgery Subscale, which complemented the general scale with items specific to quality of life (QoL) in melanoma.; The Melanoma Subscale of FACT-M included 16 questions, with response options of 0= "Not at all", 1= "a little bit", 2= "somewhat", 3= "quite a bit" and 4= "very much". The FACT-M melanoma subscale score ranged from 0 to 64, with higher scores indicating a higher quality of life in relation to melanoma.; The change from baseline in melanoma subscale scores was calculated. A positive change from baseline indicated improvement.	From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
Secondary	Randomized (Part 3): Change From Baseline in EuroQoL 5-level Instrument (EQ-5D-5L)- Visual Analog Scale (VAS) Score	The EQ-5D-5L is a standardized questionnaire used to assess health-related quality of life, and it includes a Visual Analog Scale (VAS). The VAS score is obtained by asking the individual to rate their current health status on a scale from 0 to 100, where 0 represents the worst possible health state and 100 represents the best possible health state.; The change from baseline in EQ-5D-5L VAS score was calculated. A positive change from baseline indicates improvement in the health status.	From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
Secondary	Randomized (Part 3): PFS as Per Investigator's Assessment by RECIST 1.1 by PD-L1 Expression	PFS was defined as the time from the date of first dose to the date of the first documented radiological progression as per investigator's assessment using RECIST 1.1 response criteria or death due to any cause. The distribution of PFS was estimated using the KM method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment.; PFS analysis was performed by PD-L1 status (positive, negative) where a positive status was defined as having = 1% expression and a negative status was defined as having < 1% expression.	Up to disease progression or death due to any cause, up to 2.8 years (Part 3)
Secondary	Randomized (Part 3): OS by PD-L1 Expression	OS is defined as the time from date of randomization to date of death due to any cause.; OS analysis will be performed by PD-L1 subgroup (positive, negative) where a positive status is defined as having = 1% expression and a negative status is defined as having < 1% expression.	Up to death due to any cause, up to 5 years
Secondary	Spartalizumab Anti-drug Antibody (ADA) Prevalence at Baseline	Spartalizumab ADA prevalence at baseline was calculated as the percentage of participants who had an spartalizumab ADA positive result at baseline.	Baseline
Secondary	Spartalizumab ADA Incidence	Spartalizumab ADA incidence was calculated as the percentage of participants who were treatment-induced spartalizumab ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted spartalizumab ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)	Throughout study until 150 days after the last dose of spartalizumab, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3).
Secondary	Trough Concentration (Ctrough) for Spartalizumab	Ctrough for spartalizumab refers to the serum concentration of spartalizumab immediately prior to the administration of a dose of spartalizumab on Day 1 of Cycle 2 and later cycles.	Pre-infusion on Day 1 of each Cycle starting from Cycle 2, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days
Secondary	Pre-dose Plasma Concentration for Dabrafenib	Plasma concentration of dabrafenib immediately prior to the administration of a dose of dabrafenib.	Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days
Secondary	Pre-dose Plasma Concentration for Trametinib	Plasma concentration of trametinib immediately prior to the administration of a dose of trametinib.	Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days
Secondary	Number of Participants With Dose Interruptions	Number of participants with dose interruptions for spartalizumab, dabrafenib and trametinib	From baseline to end of treatment, up to 5 years
Secondary	Number of Participants With Dose Reductions	Number of patients with dose reductions for spartalizumab, dabrafenib and trametinib	From baseline to end of treatment, up to 5 years
Secondary	Relative Dose Intensity	Relative dose intensity for spartalizumab, dabrafenib and trametinib computed as the ratio of dose intensity and planned dose intensity	From baseline to end of treatment, up to 5 years