A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma
NCT ID: NCT02967692
Last Updated: 2025-09-18
Study Results
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View full resultsBasic Information
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TERMINATED
PHASE3
568 participants
INTERVENTIONAL
2017-02-17
2024-08-21
Brief Summary
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Detailed Description
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* 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).
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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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).
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
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
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).
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
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
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)
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
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
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)
Placebo
Placebo is administered via intravenous infusion over 30 minutes once every 4 weeks
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
Interventions
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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
Placebo
Placebo is administered via intravenous infusion over 30 minutes once every 4 weeks
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
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
18 Years
100 Years
ALL
No
Sponsors
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Novartis Pharmaceuticals
INDUSTRY
Responsible Party
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Principal Investigators
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Novartis Pharmaceuticals
Role: STUDY_DIRECTOR
Novartis Pharmaceuticals
Locations
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California Cancer Associates for Research and Excellence
Encinitas, California, United States
UC Irvine Medical Center
Orange, California, United States
California Pacific Medical Center
San Francisco, California, United States
Stanford Cancer Center
Stanford, California, United States
University of Kansas Cancer Center
Westwood, Kansas, United States
Johns Hopkins U
Lutherville, Maryland, United States
Nebraska Cancer Specialists
Omaha, Nebraska, United States
NYU Laura and Isaac Perlmutter Cancer Center
New York, New York, United States
University of Pittsburgh Med Center
Pittsburgh, Pennsylvania, United States
University of Tennessee Medical Ctr
Knoxville, Tennessee, United States
Univ of TX MD Anderson Cancer Cntr
Houston, Texas, United States
Utah Cancer Specialists
Salt Lake City, Utah, United States
Novartis Investigative Site
CABA, Buenos Aires, Argentina
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CABA, Buenos Aires, Argentina
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Rosario, Santa Fe Province, Argentina
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Caba, , Argentina
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Gateshead, New South Wales, Australia
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North Sydney, New South Wales, Australia
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Greenslopes, Queensland, Australia
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Melbourne, Victoria, Australia
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Nedlands, Western Australia, Australia
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Innsbruck, Tyrol, Austria
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Graz, , Austria
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Linz, , Austria
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Salzburg, , Austria
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Sankt Pölten, , Austria
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Brussels, , Belgium
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Brussels, , Belgium
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Curitiba, Paraná, Brazil
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Porto Alegre, Rio Grande do Sul, Brazil
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São Paulo, São Paulo, Brazil
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Rio de Janeiro, , Brazil
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Plovdiv, , Bulgaria
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Sofia, , Bulgaria
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Vancouver, British Columbia, Canada
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Toronto, Ontario, Canada
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Montreal, Quebec, Canada
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Montreal, Quebec, Canada
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Sherbrooke, Quebec, Canada
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Temuco, Región de la Araucanía, Chile
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Santiago, , Chile
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Santiago, , Chile
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Brno, Czech Republic, Czechia
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Zlín, Czech Republic, Czechia
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Hradec Králové, CZE, Czechia
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Ostrava, Poruba, Czechia
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Olomouc, , Czechia
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Prague, , Czechia
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Prague, , Czechia
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Aarhus N, , Denmark
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Limoges, Haute Vienne, France
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Amiens, , France
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Besançon, , France
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Bobigny, , France
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Bordeaux, , France
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Boulogne-Billancourt, , France
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Caen, , France
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Clermont-Ferrand, , France
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Dijon, , France
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Grenoble, , France
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Le Mans, , France
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Lille, , France
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Lorient, , France
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Lyon, , France
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Marseille, , France
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Mulhouse, , France
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Nice, , France
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Paris, , France
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Pierre-Bénite, , France
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Poitiers, , France
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Reims, , France
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Rouen, , France
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Strasbourg, , France
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Toulouse, , France
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Vandœuvre-lès-Nancy, , France
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Villejuif, , France
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Mannheim, Baden-Wurttemberg, Germany
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Regensburg, Bavaria, Germany
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Leipzig, Saxony, Germany
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Halle, Saxony-Anhalt, Germany
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Berlin, , Germany
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Berlin, , Germany
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Bonn, , Germany
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Chemnitz, , Germany
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Dresden, , Germany
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Düsseldorf, , Germany
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Erfurt, , Germany
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Essen, , Germany
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Freiburg im Breisgau, , Germany
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Gera, , Germany
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Hamburg, , Germany
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Hanover, , Germany
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Heidelberg, , Germany
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Homburg, , Germany
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Kiel, , Germany
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Mainz, , Germany
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Marburg, , Germany
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Minden, , Germany
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München, , Germany
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Münster, , Germany
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Stade, , Germany
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Tübingen, , Germany
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Athens, , Greece
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Athens, , Greece
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Budapest, , Hungary
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Debrecen, , Hungary
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Szeged, , Hungary
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Haifa, , Israel
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Jerusalem, , Israel
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Ramat Gan, , Israel
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Bari, BA, Italy
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Bergamo, BG, Italy
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Bologna, BO, Italy
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Brescia, BS, Italy
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Meldola, FC, Italy
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Genova, GE, Italy
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Monza, MB, Italy
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Milan, MI, Italy
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Milan, MI, Italy
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Modena, MO, Italy
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Padua, PD, Italy
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Roma, RM, Italy
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Siena, SI, Italy
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Candiolo, TO, Italy
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Torino, TO, Italy
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Verona, VR, Italy
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Napoli, , Italy
Kyushu University Hospital
Fukuoka, Fukuoka, Japan
Kyoto University Hospital
Sakyo Ku, Kyoto, Japan
Osaka International Cancer Institute
Osaka, Osaka, Japan
Tokyo Metropolitan Komagome Hospital
Bunkyo Ku, Tokyo, Japan
National Cancer Hospital
Chuo Ku, Tokyo, Japan
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León, Guanajuato, Mexico
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Guadalajara, Jalisco, Mexico
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Mexico City, Mexico City, Mexico
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Leiden, South Holland, Netherlands
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Amersfroort, , Netherlands
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Oslo, , Norway
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Gdansk, , Poland
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Warsaw, , Poland
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Lisbon, , Portugal
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Porto, , Portugal
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Chelyabinsk, , Russia
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Moscow, , Russia
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Moscow, , Russia
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Nizhny Novgorod, , Russia
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Omsk, , Russia
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Saint Petersburg, , Russia
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Saint Petersburg, , Russia
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Samara, , Russia
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Málaga, Andalusia, Spain
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Seville, Andalusia, Spain
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Jerez de la Frontera, Cadiz, Spain
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Badalona, Catalonia, Spain
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Barcelona, Catalonia, Spain
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A Coruña, Galicia, Spain
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Oviedo, Principality of Asturias, Spain
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Valencia, Valencia, Spain
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Las Palmas de Gran Canaria, , Spain
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Madrid, , Spain
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Madrid, , Spain
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Madrid, , Spain
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Madrid, , Spain
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Gothenburg, , Sweden
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Lund, , Sweden
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Stockholm, , Sweden
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Aarau, Canton of Aargau, Switzerland
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Zurich, , Switzerland
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Songkhla, Hat Yai, Thailand
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Bangkok, , Thailand
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Truro, Cornwall, United Kingdom
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Guildford, Surrey, United Kingdom
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Sutton, Surrey, United Kingdom
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Leicester, , United Kingdom
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London, , United Kingdom
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Manchester, , United Kingdom
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Middlesbrough, , United Kingdom
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Preston, , United Kingdom
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Rickmansworth Road, , United Kingdom
Countries
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References
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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.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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2016-002794-35
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
CPDR001F2301
Identifier Type: -
Identifier Source: org_study_id
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