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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
2 other identifiers
interventional
568
28 countries
174
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Feb 2017
Longer than P75 for phase_3
174 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 16, 2016
CompletedFirst Posted
Study publicly available on registry
November 18, 2016
CompletedStudy Start
First participant enrolled
February 17, 2017
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 11, 2020
CompletedResults Posted
Study results publicly available
July 24, 2023
CompletedStudy Completion
Last participant's last visit for all outcomes
August 21, 2024
CompletedSeptember 18, 2025
September 1, 2025
3.5 years
November 16, 2016
June 26, 2023
September 1, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (4)
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 Outcomes (20)
Overall Survival (OS)
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
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
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
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
From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
- +15 more secondary outcomes
Study Arms (4)
Part 1: Safety run-in Cohort
EXPERIMENTALIn 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).
Part 2: Biomarker cohort
EXPERIMENTALIn 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).
Part 3- Arm 1: Spartalizumab in combination with dabrafenib and trametinib
EXPERIMENTALIn 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)
Part 3- Arm 2: Placebo in combination with dabrafenib and trametinib
PLACEBO COMPARATORIn 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)
Interventions
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
Placebo is administered via intravenous infusion over 30 minutes once every 4 weeks
Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.
Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions
Eligibility Criteria
You may qualify if:
- Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
- Aspartate transaminase (AST) \< 2.5Ă— ULN and Alanine transaminase (ALT) \< 2.5Ă— 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
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (179)
California Cancer Associates for Research and Excellence
Encinitas, California, 92024, United States
UC Irvine Medical Center
Orange, California, 92613-4091, United States
California Pacific Medical Center
San Francisco, California, 94115, United States
Stanford Cancer Center
Stanford, California, 94305, United States
University of Kansas Cancer Center
Westwood, Kansas, 66205, United States
Johns Hopkins U
Lutherville, Maryland, 21093, United States
Nebraska Cancer Specialists
Omaha, Nebraska, 68130, United States
NYU Laura and Isaac Perlmutter Cancer Center
New York, New York, 10016, United States
University of Pittsburgh Med Center
Pittsburgh, Pennsylvania, 15213, United States
University of Tennessee Medical Ctr
Knoxville, Tennessee, 37920, United States
Univ of TX MD Anderson Cancer Cntr
Houston, Texas, 77030, United States
Utah Cancer Specialists
Salt Lake City, Utah, 84106, United States
Novartis Investigative Site
CABA, Buenos Aires, C1125ABD, Argentina
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CABA, Buenos Aires, C1426ANZ, Argentina
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Rosario, Santa Fe Province, S2000KZE, Argentina
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Caba, C1431FWO, Argentina
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Gateshead, New South Wales, 2290, Australia
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North Sydney, New South Wales, 2060, Australia
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Greenslopes, Queensland, 4120, Australia
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Melbourne, Victoria, 3004, Australia
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Nedlands, Western Australia, 6009, Australia
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Innsbruck, Tyrol, 6020, Austria
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Graz, 8036, Austria
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Linz, 4020, Austria
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Salzburg, A-5020, Austria
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Sankt Pölten, 3100, Austria
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Brussels, 1090, Belgium
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Brussels, 1200, Belgium
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Curitiba, ParanĂ¡, 80530 010, Brazil
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Porto Alegre, Rio Grande do Sul, 90035-003, Brazil
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SĂ£o Paulo, SĂ£o Paulo, 01246 000, Brazil
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Rio de Janeiro, 20560-120, Brazil
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Plovdiv, 4004, Bulgaria
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Sofia, 1303, Bulgaria
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Vancouver, British Columbia, V5Z 4E6, Canada
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Toronto, Ontario, M4N 3M5, Canada
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Montreal, Quebec, H3T 1E2, Canada
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Montreal, Quebec, H4A 3J1, Canada
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Sherbrooke, Quebec, J1H 5N4, Canada
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Temuco, RegiĂ³n de la AraucanĂa, 4810469, Chile
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Santiago, 7500921, Chile
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Santiago, 8420383, Chile
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Brno, Czech Republic, 656 53, Czechia
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ZlĂn, Czech Republic, 762 75, Czechia
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Hradec KrĂ¡lovĂ©, CZE, 500 05, Czechia
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Ostrava, Poruba, 708 52, Czechia
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Olomouc, 779 00, Czechia
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Prague, 100 34, Czechia
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Prague, 12808, Czechia
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Aarhus N, 8200, Denmark
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Limoges, Haute Vienne, 87000, France
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Amiens, 80054, France
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Besançon, 25030, France
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Clermont-Ferrand, 63003, France
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Le Mans, 72000, France
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Lyon, 69373, France
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VandÅ“uvre-lès-Nancy, 54519, France
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Mannheim, Baden-Wurttemberg, 68305, Germany
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Halle, Saxony-Anhalt, 06120, Germany
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Essen, 45147, Germany
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Freiburg im Breisgau, 79106, Germany
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Gera, 07548, Germany
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Hanover, 30625, Germany
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Mainz, 55131, Germany
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Marburg, 35039, Germany
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Minden, 32429, Germany
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MĂ¼nchen, 81377, Germany
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MĂ¼nster, 48157, Germany
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Stade, 21682, Germany
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TĂ¼bingen, 72076, Germany
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Athens, 115 27, Greece
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Athens, 18547, Greece
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Budapest, H 1122, Hungary
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Debrecen, 4032, Hungary
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Szeged, H 6725, Hungary
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Haifa, 3109601, Israel
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Ramat Gan, 5265601, Israel
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Bari, BA, 70124, Italy
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Bologna, BO, 40138, Italy
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Brescia, BS, 25123, Italy
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Meldola, FC, 47014, Italy
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Genova, GE, 16132, Italy
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Monza, MB, 20900, Italy
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Milan, MI, 20133, Italy
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Milan, MI, 20141, Italy
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Modena, MO, 41124, Italy
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Padua, PD, 35100, Italy
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Roma, RM, 00167, Italy
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Siena, SI, 53100, Italy
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Candiolo, TO, 10060, Italy
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Torino, TO, 10126, Italy
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Verona, VR, 37134, Italy
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Napoli, 80131, Italy
Kyushu University Hospital
Fukuoka, Fukuoka, 812-8582, Japan
Kyoto University Hospital
Sakyo Ku, Kyoto, 606 8507, Japan
Osaka International Cancer Institute
Osaka, Osaka, 541-8567, Japan
Tokyo Metropolitan Komagome Hospital
Bunkyo Ku, Tokyo, 113-8677, Japan
National Cancer Hospital
Chuo Ku, Tokyo, 104 0045, Japan
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LeĂ³n, Guanajuato, 37178, Mexico
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Guadalajara, Jalisco, 44100, Mexico
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Mexico City, Mexico City, 14080, Mexico
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Leiden, South Holland, 2333, Netherlands
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Amersfroort, 3818 ES, Netherlands
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Oslo, 0310, Norway
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Gdansk, 80 952, Poland
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Warsaw, 02 781, Poland
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Lisbon, 1099 023, Portugal
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Porto, 4200-072, Portugal
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Chelyabinsk, 454048, Russia
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Moscow, 115478, Russia
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Moscow, 143423, Russia
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Nizhny Novgorod, 603137, Russia
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Omsk, 644013, Russia
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Saint Petersburg, 197758, Russia
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Saint Petersburg, 198255, Russia
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Samara, 443011, Russia
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MĂ¡laga, Andalusia, 29010, Spain
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Seville, Andalusia, 41009, Spain
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Jerez de la Frontera, Cadiz, 11407, Spain
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Badalona, Catalonia, 08916, Spain
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Barcelona, Catalonia, 08036, Spain
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A Coruña, Galicia, 15006, Spain
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Oviedo, Principality of Asturias, 33011, Spain
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Valencia, Valencia, 46014, Spain
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Las Palmas de Gran Canaria, 35016, Spain
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Madrid, 28009, Spain
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Madrid, 28034, Spain
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Gothenburg, SE-413 45, Sweden
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Lund, 221 85, Sweden
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Stockholm, SE 171 76, Sweden
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Aarau, Canton of Aargau, 5001, Switzerland
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Zurich, 8091, Switzerland
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Songkhla, Hat Yai, 90110, Thailand
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Bangkok, 10330, Thailand
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Truro, Cornwall, TR1 3LJ, United Kingdom
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Guildford, Surrey, GU2 7XX, United Kingdom
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Sutton, Surrey, SM2 5PT, United Kingdom
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Leicester, LE1 5WW, United Kingdom
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London, NW3 2QG, United Kingdom
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Manchester, M20 2BX, United Kingdom
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Middlesbrough, TS4 3BW, United Kingdom
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Preston, PR2 9HT, United Kingdom
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Rickmansworth Road, WD187HT, United Kingdom
Related Publications (3)
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.
PMID: 35728875DERIVEDDummer 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.
PMID: 35030011DERIVEDDummer 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.
PMID: 33020648DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Results Point of Contact
- Title
- Study Director
- Organization
- Novartis Pharmaceuticals
Study Officials
- STUDY DIRECTOR
Novartis Pharmaceuticals
Novartis Pharmaceuticals
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Masking Details
- Part 1 and Part 2 are open- label. Part 3 is double-blind and randomized.
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
November 16, 2016
First Posted
November 18, 2016
Study Start
February 17, 2017
Primary Completion
August 11, 2020
Study Completion
August 21, 2024
Last Updated
September 18, 2025
Results First Posted
July 24, 2023
Record last verified: 2025-09
Data Sharing
- IPD Sharing
- Will share
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