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

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

The purpose of this study was to evaluate safety and efficacy of the combination of an anti-PD-1 antibody (PDR001), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in patients with BRAF V600 mutant, unresectable and metastatic melanoma.

Study Overview

• Status: Terminated
• Conditions: Melanoma
• Intervention / Treatment: Biological: Spartalizumab; Drug: Dabrafenib; Drug: Trametinib; Other: Placebo

Detailed Description

This study was designed as a phase III, multi-center study consisting of 3 parts:

• Part 1: Safety run-in part The safety run-in part aimed to determine the recommended regimen of PDR001 in combination with dabrafenib and trametinib for previously untreated patients with BRAF V600 mutant unresectable or metastatic melanoma (stage IIIC/IV). 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: Biomarker cohort Part 2 was run to explore changes in the immune microenvironment and biomarker modulations upon treatment with the combination of dabrafenib, trametinib and PDR001. 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 received PDR001 (spartalizumab) at a dosage of 400 mg Q4W, in combination with dabrafenib (150 mg BID) and trametinib (2 mg QD).
• Part 3: Double-blind, randomized, placebo-controlled part Part 3 was comparing 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 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 discontinued study treatment without disease progression as per RECIST 1.1 continued 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 entered 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).

• Study Type: Interventional
• Enrollment (Actual): 568
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1431FWO
    • Novartis Investigative Site
  • Buenos Aires
    • CABA, Buenos Aires, Argentina, C1125ABD
      • Novartis Investigative Site
    • CABA, Buenos Aires, Argentina, C1426ANZ
      • Novartis Investigative Site
  • Santa Fe Province
    • Rosario, Santa Fe Province, Argentina, S2000KZE
      • Novartis Investigative Site
• Australia
  • New South Wales
    • Gateshead, New South Wales, Australia, 2290
      • Novartis Investigative Site
    • North Sydney, New South Wales, Australia, 2060
      • Novartis Investigative Site
  • Queensland
    • Greenslopes, Queensland, Australia, 4120
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Austria
  • Graz, Austria, 8036
    • Novartis Investigative Site
  • Linz, Austria, 4020
    • Novartis Investigative Site
  • Salzburg, Austria, A-5020
    • Novartis Investigative Site
  • Sankt Pölten, Austria, 3100
    • Novartis Investigative Site
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Novartis Investigative Site
• Belgium
  • Brussels, Belgium, 1200
    • Novartis Investigative Site
  • Brussels, Belgium, 1090
    • Novartis Investigative Site
• Brazil
  • Rio de Janeiro, Brazil, 20560-120
    • Novartis Investigative Site
  • Paraná
    • Curitiba, Paraná, Brazil, 80530 010
      • Novartis Investigative Site
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90035-003
      • Novartis Investigative Site
  • São Paulo
    • São Paulo, São Paulo, Brazil, 01246 000
      • Novartis Investigative Site
• Bulgaria
  • Plovdiv, Bulgaria, 4004
    • Novartis Investigative Site
  • Sofia, Bulgaria, 1303
    • Novartis Investigative Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Novartis Investigative Site
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H3T 1E2
      • Novartis Investigative Site
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Novartis Investigative Site
• Chile
  • Santiago, Chile, 8420383
    • Novartis Investigative Site
  • Santiago, Chile, 7500921
    • Novartis Investigative Site
  • Región de la Araucanía
    • Temuco, Región de la Araucanía, Chile, 4810469
      • Novartis Investigative Site
• Czechia
  • Olomouc, Czechia, 779 00
    • Novartis Investigative Site
  • Prague, Czechia, 100 34
    • Novartis Investigative Site
  • Prague, Czechia, 12808
    • Novartis Investigative Site
  • CZE
    • Hradec Králové, CZE, Czechia, 500 05
      • Novartis Investigative Site
  • Czech Republic
    • Brno, Czech Republic, Czechia, 656 53
      • Novartis Investigative Site
    • Zlín, Czech Republic, Czechia, 762 75
      • Novartis Investigative Site
  • Poruba
    • Ostrava, Poruba, Czechia, 708 52
      • Novartis Investigative Site
• Denmark
  • Aarhus N, Denmark, 8200
    • Novartis Investigative Site
• France
  • Amiens, France, 80054
    • Novartis Investigative Site
  • Besançon, France, 25030
    • Novartis Investigative Site
  • Bobigny, France, 93009
    • Novartis Investigative Site
  • Bordeaux, France, 33075
    • Novartis Investigative Site
  • Boulogne-Billancourt, France, 92104
    • Novartis Investigative Site
  • Caen, France, 14033
    • Novartis Investigative Site
  • Clermont-Ferrand, France, 63003
    • Novartis Investigative Site
  • Dijon, France, 21034
    • Novartis Investigative Site
  • Grenoble, France, 38043
    • Novartis Investigative Site
  • Le Mans, France, 72000
    • Novartis Investigative Site
  • Lille, France, 59037
    • Novartis Investigative Site
  • Lorient, France, 56322
    • Novartis Investigative Site
  • Lyon, France, 69373
    • Novartis Investigative Site
  • Marseille, France, 13885
    • Novartis Investigative Site
  • Mulhouse, France, 68070
    • Novartis Investigative Site
  • Nice, France, 06202
    • Novartis Investigative Site
  • Paris, France, 75475
    • Novartis Investigative Site
  • Pierre-Bénite, France, 69495
    • Novartis Investigative Site
  • Poitiers, France, 86021
    • Novartis Investigative Site
  • Reims, France, 51092
    • Novartis Investigative Site
  • Rouen, France, 76031
    • Novartis Investigative Site
  • Strasbourg, France, 67091
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
  • Vandœuvre-lès-Nancy, France, 54519
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Novartis Investigative Site
  • Haute Vienne
    • Limoges, Haute Vienne, France, 87000
      • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Berlin, Germany, 13578
    • Novartis Investigative Site
  • Bonn, Germany, 53105
    • Novartis Investigative Site
  • Chemnitz, Germany, 09117
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Düsseldorf, Germany, 40225
    • Novartis Investigative Site
  • Erfurt, Germany, 99089
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Freiburg im Breisgau, Germany, 79106
    • Novartis Investigative Site
  • Gera, Germany, 07548
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Hanover, Germany, 30625
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Homburg, Germany, 66421
    • Novartis Investigative Site
  • Kiel, Germany, 24105
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Marburg, Germany, 35039
    • Novartis Investigative Site
  • Minden, Germany, 32429
    • Novartis Investigative Site
  • München, Germany, 81377
    • Novartis Investigative Site
  • Münster, Germany, 48157
    • Novartis Investigative Site
  • Stade, Germany, 21682
    • Novartis Investigative Site
  • Tübingen, Germany, 72076
    • Novartis Investigative Site
  • Baden-Wurttemberg
    • Mannheim, Baden-Wurttemberg, Germany, 68305
      • Novartis Investigative Site
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Novartis Investigative Site
  • Saxony
    • Leipzig, Saxony, Germany, 04103
      • Novartis Investigative Site
  • Saxony-Anhalt
    • Halle, Saxony-Anhalt, Germany, 06120
      • Novartis Investigative Site
• Greece
  • Athens, Greece, 115 27
    • Novartis Investigative Site
  • Athens, Greece, 18547
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H 1122
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Szeged, Hungary, H 6725
    • Novartis Investigative Site
• Israel
  • Haifa, Israel, 3109601
    • Novartis Investigative Site
  • Jerusalem, Israel, 9112001
    • Novartis Investigative Site
  • Ramat Gan, Israel, 5265601
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • BA
    • Bari, BA, Italy, 70124
      • Novartis Investigative Site
  • BG
    • Bergamo, BG, Italy, 24127
      • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • FC
    • Meldola, FC, Italy, 47014
      • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • MB
    • Monza, MB, Italy, 20900
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20133
      • Novartis Investigative Site
    • Milan, MI, Italy, 20141
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41124
      • Novartis Investigative Site
  • PD
    • Padua, PD, Italy, 35100
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00167
      • Novartis Investigative Site
  • SI
    • Siena, SI, Italy, 53100
      • Novartis Investigative Site
  • TO
    • Candiolo, TO, Italy, 10060
      • Novartis Investigative Site
    • Torino, TO, Italy, 10126
      • Novartis Investigative Site
  • VR
    • Verona, VR, Italy, 37134
      • Novartis Investigative Site
• Japan
  • Fukuoka
    • Fukuoka, Fukuoka, Japan, 812-8582
      • Kyushu University Hospital
  • Kyoto
    • Sakyo Ku, Kyoto, Japan, 606 8507
      • Kyoto University Hospital
  • Osaka
    • Osaka, Osaka, Japan, 541-8567
      • Osaka International Cancer Institute
  • Tokyo
    • Bunkyo Ku, Tokyo, Japan, 113-8677
      • Tokyo Metropolitan Komagome Hospital
    • Chuo Ku, Tokyo, Japan, 104 0045
      • National Cancer Hospital
• Mexico
  • Guanajuato
    • León, Guanajuato, Mexico, 37178
      • Novartis Investigative Site
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44100
      • Novartis Investigative Site
  • Mexico City
    • Mexico City, Mexico City, Mexico, 14080
      • Novartis Investigative Site
• Netherlands
  • Amersfroort, Netherlands, 3818 ES
    • Novartis Investigative Site
  • South Holland
    • Leiden, South Holland, Netherlands, 2333
      • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0310
    • Novartis Investigative Site
• Poland
  • Gdansk, Poland, 80 952
    • Novartis Investigative Site
  • Warsaw, Poland, 02 781
    • Novartis Investigative Site
• Portugal
  • Lisbon, Portugal, 1099 023
    • Novartis Investigative Site
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
• Russia
  • Chelyabinsk, Russia, 454048
    • Novartis Investigative Site
  • Moscow, Russia, 115478
    • Novartis Investigative Site
  • Moscow, Russia, 143423
    • Novartis Investigative Site
  • Nizhny Novgorod, Russia, 603137
    • Novartis Investigative Site
  • Omsk, Russia, 644013
    • Novartis Investigative Site
  • Saint Petersburg, Russia, 197758
    • Novartis Investigative Site
  • Saint Petersburg, Russia, 198255
    • Novartis Investigative Site
  • Samara, Russia, 443011
    • Novartis Investigative Site
• Spain
  • Las Palmas de Gran Canaria, Spain, 35016
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Madrid, Spain, 28050
    • Novartis Investigative Site
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Madrid, Spain, 28222
    • Novartis Investigative Site
  • Andalusia
    • Málaga, Andalusia, Spain, 29010
      • Novartis Investigative Site
    • Seville, Andalusia, Spain, 41009
      • Novartis Investigative Site
  • Cadiz
    • Jerez de la Frontera, Cadiz, Spain, 11407
      • Novartis Investigative Site
  • Catalonia
    • Badalona, Catalonia, Spain, 08916
      • Novartis Investigative Site
    • Barcelona, Catalonia, Spain, 08036
      • Novartis Investigative Site
  • Galicia
    • A Coruña, Galicia, Spain, 15006
      • Novartis Investigative Site
  • Principality of Asturias
    • Oviedo, Principality of Asturias, Spain, 33011
      • Novartis Investigative Site
  • Valencia
    • Valencia, Valencia, Spain, 46014
      • Novartis Investigative Site
• Sweden
  • Gothenburg, Sweden, SE-413 45
    • Novartis Investigative Site
  • Lund, Sweden, 221 85
    • Novartis Investigative Site
  • Stockholm, Sweden, SE 171 76
    • Novartis Investigative Site
• Switzerland
  • Zurich, Switzerland, 8091
    • Novartis Investigative Site
  • Canton of Aargau
    • Aarau, Canton of Aargau, Switzerland, 5001
      • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Hat Yai
    • Songkhla, Hat Yai, Thailand, 90110
      • Novartis Investigative Site
• United Kingdom
  • Leicester, United Kingdom, LE1 5WW
    • Novartis Investigative Site
  • London, United Kingdom, NW3 2QG
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 2BX
    • Novartis Investigative Site
  • Middlesbrough, United Kingdom, TS4 3BW
    • Novartis Investigative Site
  • Preston, United Kingdom, PR2 9HT
    • Novartis Investigative Site
  • Rickmansworth Road, United Kingdom, WD187HT
    • Novartis Investigative Site
  • Cornwall
    • Truro, Cornwall, United Kingdom, TR1 3LJ
      • Novartis Investigative Site
  • Surrey
    • Guildford, Surrey, United Kingdom, GU2 7XX
      • Novartis Investigative Site
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Novartis Investigative Site
• United States
  • California
    • Encinitas, California, United States, 92024
      • California Cancer Associates for Research and Excellence
    • Orange, California, United States, 92613-4091
      • UC Irvine Medical Center
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
    • Stanford, California, United States, 94305
      • Stanford Cancer Center
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Maryland
    • Lutherville, Maryland, United States, 21093
      • Johns Hopkins U
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Nebraska Cancer Specialists
  • New York
    • New York, New York, United States, 10016
      • NYU Laura and Isaac Perlmutter Cancer Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Med Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Ctr
  • Texas
    • Houston, Texas, United States, 77030
      • Univ of TX MD Anderson Cancer Cntr
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Safety run-in Cohort; In Part 1, participants are treated at different dose levels to determine the recommended Phase 3 regimen of spartalizumab in combination with dabrafenib and trametinib. The starting dose of spartalizumab is 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).	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 Names: PDR001; Drug: Dabrafenib; Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.; Drug: Trametinib; Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions
Experimental: Part 2: Biomarker cohort; In Part 2, participants are treated with spartalizumab 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).	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 Names: PDR001; Drug: Dabrafenib; Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.; Drug: Trametinib; Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions
Experimental: Part 3- Arm 1: Spartalizumab in combination with dabrafenib and trametinib; In Part 3, participants are randomized to receive spartalizumab at the RP3R identified in Part 1 (400 mg Q4W) in combination with approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)	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 Names: PDR001; Drug: Dabrafenib; Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.; Drug: Trametinib; Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions
Placebo Comparator: Part 3- Arm 2: Placebo in combination with dabrafenib and trametinib; In Part 3, participants are randomized to receive matching placebo in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)	Drug: Dabrafenib; Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.; Drug: Trametinib; Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions; Other: Placebo; Placebo is administered via intravenous infusion over 30 minutes once every 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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).
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
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
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
Overall Survival (OS)	Overall survival was 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 7 years
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
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)
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
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)
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)
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)
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)
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)
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)
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)
Randomized (Part 3): OS by PD-L1 Expression	Overall survival was defined as the time from date of randomization to date of death due to any cause. OS analysis was performed by PD-L1 subgroup (positive, negative) where a positive status was defined as having ≥ 1% expression and a negative status was defined as having < 1% expression.	Up to death due to any cause, assessed up to approximately 7 years
Number of Participants With Dose Interruptions	Number of participants with dose interruptions for spartalizumab, dabrafenib and trametinib	From baseline to end of treatment, assessed up to approximately 7 years
Number of Participants With Dose Reductions	Number of patients with dose reductions for spartalizumab, dabrafenib and trametinib	From baseline to end of treatment, assessed up to approximately 7 years
Relative Dose Intensity	Relative dose intensity for spartalizumab, dabrafenib and trametinib computed as the ratio (expressed as percentage) of dose intensity and planned dose intensity: Spartalizumab (PDR001) = [Dose intensity (mg/4W) / planned dose intensity (mg/4W)]*100.; Trametinib and Dabrafenib = [Dose intensity (mg/day) / planned dose intensity (mg/day)]*100.	From baseline to end of treatment, assessed up to approximately 7 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Tawbi HA, Robert C, Brase JC, Gusenleitner D, Gasal E, Garrett J, Savchenko A, Gorgun G, Flaherty KT, Ribas A, Dummer R, Schadendorf D, Long GV, Nathan PD, Ascierto PA. Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i). J Immunother Cancer. 2022 Jun;10(6):e004226. doi: 10.1136/jitc-2021-004226.
• Dummer R, Long GV, Robert C, Tawbi HA, Flaherty KT, Ascierto PA, Nathan PD, Rutkowski P, Leonov O, Dutriaux C, Mandala M, Lorigan P, Ferrucci PF, Grob JJ, Meyer N, Gogas H, Stroyakovskiy D, Arance A, Brase JC, Green S, Haas T, Masood A, Gasal E, Ribas A, Schadendorf D. Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma. J Clin Oncol. 2022 May 1;40(13):1428-1438. doi: 10.1200/JCO.21.01601. Epub 2022 Jan 14.
• Dummer R, Lebbe C, Atkinson V, Mandala M, Nathan PD, Arance A, Richtig E, Yamazaki N, Robert C, Schadendorf D, Tawbi HA, Ascierto PA, Ribas A, Flaherty KT, Pakhle N, Campbell CD, Gusenleitner D, Masood A, Brase JC, Gasal E, Long GV. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Nat Med. 2020 Oct;26(10):1557-1563. doi: 10.1038/s41591-020-1082-2. Epub 2020 Oct 5.

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2017
• Primary Completion (Actual): August 11, 2020
• Study Completion (Actual): August 21, 2024

Study Registration Dates

• First Submitted: November 16, 2016
• First Submitted That Met QC Criteria: November 16, 2016
• First Posted (Estimated): November 18, 2016

Study Record Updates

• Last Update Posted (Estimated): September 18, 2025
• Last Update Submitted That Met QC Criteria: September 1, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: immunotherapy; PD-1; BRAF V600; melanoma; trametinib; dabrafenib; anti-PD-1; skin cancer; combination treatment; Spartalizumab (PDR001); PD 1 inhibitor; anti PD1; malignant skin cancer; unresectable BRAF V600 mutated melanoma; metastatic BRAF V600 mutated melanoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin and Connective Tissue Diseases; Melanoma; Skin Neoplasms; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs; dabrafenib; trametinib; spartalizumab
• Other Study ID Numbers: CPDR001F2301; 2016-002794-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No