MelanomaPhase 3COMBI-vNCT01597908
Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma
A Phase 3 study testing Dabrafenib, Vemurafenib and Trametinib in people with Melanoma, run by Novartis Pharmaceuticals at 205 sites in 28 countries.
Trial summary
This was a two-arm, open-label, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy with vemurafenib. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Dabrafenib, Vemurafenib and Trametinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 704 participants
- Where
- 205 sitesin 28 countries
- Study dates
- 4 Jun 2012to 25 Apr 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- >= 18 years of age
- Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma
- Measurable disease according to RECIST 1.1
- Women of childbearing potential with negative serum pregnancy test prior to randomisation
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- Adequate baseline organ function
Who cannot join
- Any prior use of a BRAF or MEK inhibitor
- Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed
- History of another malignancy (except subjects who have been disease free for 3 years or with a history of completely resected non-melanoma skin cancer)
- Known HIV, HBV, HCV infection (except chronic or cleared HBV and HCV infection which will be allowed)
- Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for >= 12 weeks prior to randomisation or if no longer present are confirmed no evidence of disease for >= 12 weeks, and are asymptomatic with no corticosteroid requirements for >= 4 weeks prior to randomisation, and no enzyme inducing anticonvulsants for >= 4 weeks prior to randomisation
- History or evidence of cardiovascular risk (LVEF < LLN; QTcB >= 480 msec; blood pressure or systolic >=140 mmHg or diastolic >= 90 mmHg which cannot be controlled by anti-hypertensive therapy)
- History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
Trial locations and contacts
205 sites in 28 countries.
205 sites in 28 countries
United States36 sites
Novartis Investigative Site
Ann Arbor, Michigan, 48109
Novartis Investigative Site
Atlanta, Georgia, 30322
Novartis Investigative Site
Atlanta, Georgia, 30341
Novartis Investigative Site
Aurora, Colorado, 80010
Novartis Investigative Site
Bend, Oregon, 97701
Novartis Investigative Site
Beverly Hills, California, 90211
Novartis Investigative Site
Birmingham, Alabama, 35243
Novartis Investigative Site
Burlington, Vermont, 05403
Novartis Investigative Site
Chapel Hill, North Carolina, 27599-7600
Novartis Investigative Site
Charleston, South Carolina, 29425
Novartis Investigative Site
Charlotte, North Carolina, 28204
Novartis Investigative Site
Charlottesville, Virginia, 22903
Novartis Investigative Site
Cincinnati, Ohio, 45219
Novartis Investigative Site
Columbus, Ohio, 43210
Novartis Investigative Site
Dallas, Texas, 75246
Novartis Investigative Site
Durham, North Carolina, 27710
Novartis Investigative Site
Fridley, Minnesota, 55432
Novartis Investigative Site
Gilbert, Arizona, 85234
Novartis Investigative Site
Greenville, South Carolina, 29605
Novartis Investigative Site
Hackensack, New Jersey, 07601
Novartis Investigative Site
Iowa City, Iowa, 52242
Novartis Investigative Site
Jacksonville, Florida, 32204
Novartis Investigative Site
Las Vegas, Nevada, 89148
Novartis Investigative Site
Miami Beach, Florida, 33140
Novartis Investigative Site
Milwaukee, Wisconsin, 53226
Novartis Investigative Site
Nashville, Tennessee, 37232
Novartis Investigative Site
New Brunswick, New Jersey, 08901
Novartis Investigative Site
New York, New York, 10029
Novartis Investigative Site
Orlando, Florida, 32804
Novartis Investigative Site
Portland, Oregon, 97213
Novartis Investigative Site
Portland, Oregon, 97239
Novartis Investigative Site
Salt Lake City, Utah, 84106
Novartis Investigative Site
Salt Lake City, Utah, 84112-5550
Novartis Investigative Site
San Francisco, California, 94115
Novartis Investigative Site
St Louis, Missouri, 63110
Novartis Investigative Site
Vallejo, California, 94589
Germany25 sites
Novartis Investigative Site
Bonn, North Rhine-Westphalia, 53127
Novartis Investigative Site
Buxtehude, Lower Saxony, 21614
Novartis Investigative Site
Cologne, North Rhine-Westphalia, 50937
Novartis Investigative Site
Dresden, Saxony, 01307
Novartis Investigative Site
Erfurt, Thuringia, 99089
Novartis Investigative Site
Erlangen, Bavaria, 91054
Novartis Investigative Site
Essen, North Rhine-Westphalia, 45122
Novartis Investigative Site
Gera, Thuringia, 07548
Novartis Investigative Site
Hanover, Lower Saxony, 30625
Novartis Investigative Site
Heidelberg, Baden-Wurttemberg, 69120
Novartis Investigative Site
Heilbronn, Baden-Wurttemberg, 74078
Novartis Investigative Site
Kiel, Schleswig-Holstein, 24105
Novartis Investigative Site
Leipzig, Saxony, 04103
Novartis Investigative Site
Lübeck, Schleswig-Holstein, 23538
Novartis Investigative Site
Ludwigshafen am Rhein, Rhineland-Palatinate, 67063
Novartis Investigative Site
Magdeburg, Saxony-Anhalt, 39120
Novartis Investigative Site
Mainz, Rhineland-Palatinate, 55131
Novartis Investigative Site
Mannheim, Baden-Wurttemberg, 68167
Novartis Investigative Site
Munich, Bavaria, 80337
Novartis Investigative Site
Munich, Bavaria, 80802
Novartis Investigative Site
Munich, Bavaria, 80804
Novartis Investigative Site
Nuremberg, Bavaria, 90419
Novartis Investigative Site
Regensburg, Bavaria, 93053
Novartis Investigative Site
Tübingen, Baden-Wurttemberg, 72076
Novartis Investigative Site
Würzburg, Bavaria, 97080
Canada12 sites
Novartis Investigative Site
Calgary, Alberta, T2N 4N2
Novartis Investigative Site
Halifax, Nova Scotia, B3H 2Y9
Novartis Investigative Site
Kelowna, British Columbia, V1Y 5L3
Novartis Investigative Site
Kingston, Ontario, K7L 5P9
Novartis Investigative Site
Montreal, Quebec, H2L 4M1
Novartis Investigative Site
Oshawa, Ontario, L1G 2B9
Novartis Investigative Site
Ottawa, Ontario, K1H 8L6
Novartis Investigative Site
Québec, Quebec, G1R 2J6
Novartis Investigative Site
Toronto, Ontario, M4N 3M5
Novartis Investigative Site
Toronto, Ontario, M5G 2M9
Novartis Investigative Site
Vancouver, British Columbia, V5Z 4E6
Novartis Investigative Site
Winnipeg, Manitoba, R3E 0V9
France11 sites
Novartis Investigative Site
Bordeaux, 33075
Novartis Investigative Site
Grenoble, 38043
Novartis Investigative Site
Lille, 59037
Novartis Investigative Site
Marseille, 13385
Novartis Investigative Site
Montpellier, 34295
Novartis Investigative Site
Nantes, 44093
Novartis Investigative Site
Nice, 06202
Novartis Investigative Site
Paris, 75475
Novartis Investigative Site
Reims, 51092
Novartis Investigative Site
Rennes, 35042
Novartis Investigative Site
Villejuif, 94805
Australia9 sites
Novartis Investigative Site
Box Hill, Victoria, 3128
Novartis Investigative Site
Greenslopes, Queensland, 4120
Novartis Investigative Site
Herston, Queensland, 4029
Novartis Investigative Site
Melbourne, Victoria, 3004
Novartis Investigative Site
Nedlands, Western Australia, 6009
Novartis Investigative Site
North Sydney, New South Wales, 2060
Novartis Investigative Site
South Brisbane, Queensland, 4101
Novartis Investigative Site
Westmead, New South Wales, 2145
Novartis Investigative Site
Woodville, South Australia, 5011
Spain9 sites
Novartis Investigative Site
Barcelona, 08036
Novartis Investigative Site
Hospitalet de Llobregat, Barcelona, 08907
Novartis Investigative Site
Las Palmas de Gran Canaria, 35016
Novartis Investigative Site
Madrid, 28007
Novartis Investigative Site
Madrid, 28050
Novartis Investigative Site
Palma de Mallorca, 07010
Novartis Investigative Site
Pamplona, 31008
Novartis Investigative Site
Valencia, 46009
Novartis Investigative Site
Valencia, 46014
Belgium8 sites
Novartis Investigative Site
Brasschaat, 2930
Novartis Investigative Site
Brussels, 1090
Novartis Investigative Site
Brussels, 1200
Novartis Investigative Site
Ghent, 9000
Novartis Investigative Site
Kortrijk, 8500
Novartis Investigative Site
Leuven, 3000
Novartis Investigative Site
Namur, 5000
Novartis Investigative Site
Wilrijk, 2610
Italy8 sites
Novartis Investigative Site
Bergamo, Lombardy, 24128
Novartis Investigative Site
Genoa, Liguria, 16132
Novartis Investigative Site
Milan, Lombardy, 20133
Novartis Investigative Site
Milan, Lombardy, 20141
Novartis Investigative Site
Naples, Campania, 80131
Novartis Investigative Site
Padova, Veneto, 35128
Novartis Investigative Site
Pisa, Tuscany, 56126
Novartis Investigative Site
Rome, Lazio, 00167
Hungary7 sites
Novartis Investigative Site
Budapest, 1062
Novartis Investigative Site
Budapest, H-1122
Novartis Investigative Site
Debrecen, 4032
Novartis Investigative Site
Győr, H-9024
Novartis Investigative Site
Kaposvár, 7400
Novartis Investigative Site
Miskolc, 3526
Novartis Investigative Site
Szeged, 6720
Russia7 sites
Novartis Investigative Site
Chelyabinsk, 454087
Novartis Investigative Site
Magnitogorsk, 455001
Novartis Investigative Site
Moscow, 115478
Novartis Investigative Site
Moscow, 143423
Novartis Investigative Site
Nizhny Novgorod, 603081
Novartis Investigative Site
Ryazan, 390011
Novartis Investigative Site
Saint Petersburg, 197758
Ukraine7 sites
Novartis Investigative Site
Dnipropetrovsk, 49102
Novartis Investigative Site
Donetsk, 83092
Novartis Investigative Site
Kharkiv, 61070
Novartis Investigative Site
Kyiv, 03022
Novartis Investigative Site
Lviv, 79031
Novartis Investigative Site
Sumy, 40005
Novartis Investigative Site
Uzhhorod, 88017
United Kingdom7 sites
Novartis Investigative Site
Cambridge, CB2 0QQ
Novartis Investigative Site
Glasgow, G12 0YN
Novartis Investigative Site
London, NW3 2QG
Novartis Investigative Site
London, SE1 7EH
Novartis Investigative Site
Manchester, M20 4BX
Novartis Investigative Site
Southampton, SO16 6YD
Novartis Investigative Site
Swansea, SA2 8QA
Argentina6 sites
Novartis Investigative Site
Buenos Aires, C1121ABE
Novartis Investigative Site
Capital Federal, Buenos Aires, C1426ANZ
Novartis Investigative Site
Rosario, Santa Fe Province, S2000KZE
Novartis Investigative Site
San Miguel de Tucumán, T4000IAK
Novartis Investigative Site
Santa Fe, 3000
Novartis Investigative Site
Viedma, Río Negro Province, R8500ACE
Netherlands6 sites
Novartis Investigative Site
Amsterdam, 1066 CX
Novartis Investigative Site
Amsterdam, 1081 HV
Novartis Investigative Site
Groningen, 9713 GZ
Novartis Investigative Site
Leeuwarden, 8934 AD
Novartis Investigative Site
Leiden, 2333 ZA
Novartis Investigative Site
Rotterdam, 3015 GD
Austria5 sites
Novartis Investigative Site
Graz, A-8036
Novartis Investigative Site
Innsbruck, 6020
Novartis Investigative Site
Salzburg, A-5020
Novartis Investigative Site
Vienna, 1090
Novartis Investigative Site
Vienna, A-1030
Czechia5 sites
Novartis Investigative Site
Olomouc, 775 20
Novartis Investigative Site
Ostrava, 708 52
Novartis Investigative Site
Prague, 100 34
Novartis Investigative Site
Prague, 128 08
Novartis Investigative Site
Zlín, 76275
Ireland5 sites
Novartis Investigative Site
Co.Cork
Novartis Investigative Site
Dublin, 4
Novartis Investigative Site
Dublin, 7
Novartis Investigative Site
Dublin, 9
Novartis Investigative Site
Galway
Finland4 sites
Novartis Investigative Site
Helsinki, 00029
Novartis Investigative Site
Jyväskylä, 40620
Novartis Investigative Site
Tampere, 33520
Novartis Investigative Site
Turku, 20520
Poland4 sites
Novartis Investigative Site
Gdansk, 80-215
Novartis Investigative Site
Konin, 62-500
Novartis Investigative Site
Poznan, 60-693
Novartis Investigative Site
Warsaw, 02-781
Brazil3 sites
Novartis Investigative Site
Ijuí, Rio Grande do Sul, 98700-000
Novartis Investigative Site
Itajaí, Santa Catarina, 88301-215
Novartis Investigative Site
Sao Paulo - SP, 01323-900
Denmark3 sites
Novartis Investigative Site
Arhus C, 8000
Novartis Investigative Site
Herlev, 2730
Novartis Investigative Site
Odense, 5000 C
Norway3 sites
Novartis Investigative Site
Kristiansand, 4604
Novartis Investigative Site
Lorenskog, 1478
Novartis Investigative Site
Oslo, 0310
South Korea3 sites
Novartis Investigative Site
Goyang-si, Gyeonggi-Do, 410-769
Novartis Investigative Site
Seoul, 03080
Novartis Investigative Site
Seoul, 135-710
Switzerland3 sites
Novartis Investigative Site
Basel, 4031
Novartis Investigative Site
Lausanne, 1011
Novartis Investigative Site
Zurich, 8091
Taiwan3 sites
Novartis Investigative Site
Tainan, 704
Novartis Investigative Site
Taipei, 100
Novartis Investigative Site
Taoyuan, 333
Israel2 sites
Novartis Investigative Site
Jerusalem
Novartis Investigative Site
Ramat Gan, 52621
New Zealand2 sites
Novartis Investigative Site
Christchurch, 8011
Novartis Investigative Site
Newtown, Wellington, 6002
Sweden2 sites
Novartis Investigative Site
Linköping, SE-581 85
Novartis Investigative Site
Umeå, SE-901 85
About this study
Official title: A Phase III, Randomised, Open-label Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to the BRAF Inhibitor Vemurafenib in Subjects With Unresectable (Stage IIIc) or Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma
This was a two-arm, open-label, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy with vemurafenib.
Read the detailed description
Screening/Subject eligibility: Subjects with histologically confirmed cutaneous melanoma that was either unresectable or metastatic (Stages IIIC or IV), were screened for eligibility. Eligible subjects were BRAF V600E or V600K mutation positive. Subjects who had prior systemic anti-cancer treatment in the advanced or metastatic setting were not eligible although prior systemic treatment in the adjuvant setting was allowed.
Randomization: A total of 704 subjects were randomized in a ratio of 1:1 to receive combination therapy (352 subjects) or vemurafenib treatment (352 subjects). Subjects were stratified by LDH level (> the ULN versus =< ULN) and BRAF mutation (V600E versus V600K).
Study treatment: Dabrafenib and trametinib were administered orally at their recommended doses of 150 mg b.i.d. and 2.0 mg once daily, respectively. Subjects randomized in the combination therapy arm received both the agents. Subjects randomized in the vemurafenib arm received vemurafenib at the recommended dose of 960 mg orally b.i.d. Subjects in both the arms continued treatment until disease progression, death, unacceptable toxicity, or withdrawal of consent. The protocol was amended on 07-Aug-2014 which allowed subjects who were still receiving vemurafenib to cross over to the dabrafenib and trametinib combination arm, including those subjects who were still receiving vemurafenib monotherapy treatment after disease progression. A washout period of a minimum of 7 days was considered prior to initiating dabrafenib in combination with trametinib. Subjects who experienced disease progression on the vemurafenib monotherapy arm, discontinued vemurafenib monotherapy, and subsequently received another anticancer therapy were ineligible for cross over to the dabrafenib and trametinib combination arm.
Follow-up/Study closure: After study treatment discontinuation, subjects were followed for survival and disease progression as applicable. This study completed once all the subjects had at least the 5-years of follow-up.
- Conditions
- Melanoma
- Being tested
- Dabrafenib, Vemurafenib, Trametinib
- Keywords
- BRAF inhibitor, Metastatic Melanoma, Cancer, MEK inhibitor
- Medical subject headings
- Melanoma, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DabrafenibDrug
Also called GSK2118436
Dabrafenib 150 mg twice daily orally
VemurafenibDrug
Also called Monotherapy
Vemurafenib 960 mg twice daily orally
TrametinibDrug
Also called GSK1120212
Trametinib 2 mg once daily orally
| Study group | Role | What they receive |
|---|---|---|
| Dabrafenib plus Trametinib | Experimental | BRAF inhibitor plus MEK inhibitor Receives: Drug: Dabrafenib; Drug: Trametinib |
| Vemurafenib | Active comparator | BRAF inhibitor Receives: Drug: Vemurafenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival (OS)
Overall Survival (OS) was defined as the interval of time between the date of randomization and the date of death due to any cause. For patients who did not die, OS was censored at the date of last contact.
Measured: From the date of randomization until date of death due to any cause (up to approximately 6 years)
Secondary outcomes (3)
Progression-Free Survival (PFS), as Assessed by the Investigator
Progression-free survival (PFS) was defined as the interval of time between the date of randomization and the first documented occurrence of disease progression or death due to any cause. PFS for investigator-assessed response was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression was defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation.
Measured: From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)
Overall Response Rate (ORR) During Randomized Phase, as Assessed by the Investigator
Overall response was defined as the percentage of confirmed responders (complete response [CR] + partial response [PR] per RECIST, Version 1.1) as summarized by Investigator assessment. CR was defined as the disappearance of all evidence of target lesions. PR was defined as at least a 30% reduction from Baseline in the sum of the longest diameter (LD) of all target lesions. Data were reported as those participants with measureable disease at Baseline.
Measured: From randomization until the first documented complete response or partial response (up to approximately 6 years)
Duration of Response (DOR), as Assessed by the Investigator
Duration of Response (DOR) was defined as the time from the first documented evidence of a CR (disappearance of all evidence of target lesions) or a PR (at least a 30% reduction from Baseline in the sum of the longest diameter of all target lesions) until disease progression or death due to any cause. PD was defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of at least1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Data were summarized per RECIST, Version 1.1.
Measured: From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 May 2012 (estimated)
- Study start4 Jun 2012
- Primary completion17 Apr 2014
- Study completion25 Apr 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 704 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01597908
- Sponsor's protocol ID
- 116513
- Other IDs
- CDRB436B2302, 2011-006088-23
- Acronym
- COMBI-v
- Status last verified
- Feb 2021
- First submitted
- 10 May 2012
- Last updated
- 24 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
Schadendorf D, Robert C, Dummer R, Flaherty KT, Tawbi HA, Menzies AM, Banerjee H, Lau M, Long GV. Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers. Eur J Cancer. 2021 Aug;153:234-241. doi: 10.1016/j.ejca.2021.05.005. Epub 2021 Jul 2.
PubMed 34225229Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandala M, Haanen JBAG, Lebbe C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019 Aug 15;381(7):626-636. doi: 10.1056/NEJMoa1904059. Epub 2019 Jun 4.
PubMed 31166680Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, Davies MA. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016 Dec;17(12):1743-1754. doi: 10.1016/S1470-2045(16)30578-2. Epub 2016 Nov 16.
PubMed 27864013Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, Stroyakovskiy D, Drucis K, Grange F, Chiarion-Sileni V, Rutkowski P, Lichinitser M, Levchenko E, Wolter P, Hauschild A, Long GV, Nathan P, Ribas A, Flaherty K, Sun P, Legos JJ, McDowell DO, Mookerjee B, Schadendorf D, Robert C. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015 Oct;16(13):1389-98. doi: 10.1016/S1470-2045(15)00087-X.
PubMed 26433819Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. doi: 10.1056/NEJMoa1412690. Epub 2014 Nov 16.
PubMed 25399551
Study at a glance
From the registry record, last updated by the sponsor on 24 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase III, Randomised, Open-label Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to the BRAF Inhibitor Vemurafenib in Subjects With Unresectable (Stage IIIc) or Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma
- ClinicalTrials.gov ID
- NCT01597908
- Acronym / sponsor ID
- COMBI-v / 116513
- Conditions
- Melanoma
- Keywords
- BRAF inhibitor, Metastatic Melanoma, Cancer, MEK inhibitor
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 704 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 4 Jun 2012 (actual)
- Primary completion
- 17 Apr 2014 (actual)
- Study completion
- 25 Apr 2019 (actual)
- First posted
- 14 May 2012 (estimated)
- Results
- Posted 4 Dec 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This was a two-arm, open-label, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy with vemurafenib.
Detailed description
Screening/Subject eligibility: Subjects with histologically confirmed cutaneous melanoma that was either unresectable or metastatic (Stages IIIC or IV), were screened for eligibility. Eligible subjects were BRAF V600E or V600K mutation positive. Subjects who had prior systemic anti-cancer treatment in the advanced or metastatic setting were not eligible although prior systemic treatment in the adjuvant setting was allowed.
Randomization: A total of 704 subjects were randomized in a ratio of 1:1 to receive combination therapy (352 subjects) or vemurafenib treatment (352 subjects). Subjects were stratified by LDH level (> the ULN versus =< ULN) and BRAF mutation (V600E versus V600K).
Study treatment: Dabrafenib and trametinib were administered orally at their recommended doses of 150 mg b.i.d. and 2.0 mg once daily, respectively. Subjects randomized in the combination therapy arm received both the agents. Subjects randomized in the vemurafenib arm received vemurafenib at the recommended dose of 960 mg orally b.i.d. Subjects in both the arms continued treatment until disease progression, death, unacceptable toxicity, or withdrawal of consent. The protocol was amended on 07-Aug-2014 which allowed subjects who were still receiving vemurafenib to cross over to the dabrafenib and trametinib combination arm, including those subjects who were still receiving vemurafenib monotherapy treatment after disease progression. A washout period of a minimum of 7 days was considered prior to initiating dabrafenib in combination with trametinib. Subjects who experienced disease progression on the vemurafenib monotherapy arm, discontinued vemurafenib monotherapy, and subsequently received another anticancer therapy were ineligible for cross over to the dabrafenib and trametinib combination arm.
Follow-up/Study closure: After study treatment discontinuation, subjects were followed for survival and disease progression as applicable. This study completed once all the subjects had at least the 5-years of follow-up.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dabrafenib plus Trametinib | Experimental | Drug: Dabrafenib, Drug: TrametinibBRAF inhibitor plus MEK inhibitor |
| Vemurafenib | Active comparator | Drug: VemurafenibBRAF inhibitor |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- >= 18 years of age
- Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma
- Measurable disease according to RECIST 1.1
- Women of childbearing potential with negative serum pregnancy test prior to randomisation
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Key exclusion criteria (7 listed)
- Any prior use of a BRAF or MEK inhibitor
- Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed
- History of another malignancy (except subjects who have been disease free for 3 years or with a history of completely resected non-melanoma skin cancer)
- Known HIV, HBV, HCV infection (except chronic or cleared HBV and HCV infection which will be allowed)
- Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for >= 12 weeks prior to randomisation or if no longer present are confirmed no evidence of disease for >= 12 weeks, and are asymptomatic with no corticosteroid requirements for >= 4 weeks prior to randomisation, and no enzyme inducing anticonvulsants for >= 4 weeks prior to randomisation
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DabrafenibAlso: GSK2118436Dabrafenib 150 mg twice daily orally | Drug | Dabrafenib plus Trametinib |
| VemurafenibAlso: MonotherapyVemurafenib 960 mg twice daily orally | Drug | Vemurafenib |
| TrametinibAlso: GSK1120212Trametinib 2 mg once daily orally | Drug | Dabrafenib plus Trametinib |
Primary outcome
Overall Survival (OS)
Time frame: From the date of randomization until date of death due to any cause (up to approximately 6 years)
Overall Survival (OS) was defined as the interval of time between the date of randomization and the date of death due to any cause. For patients who did not die, OS was censored at the date of last contact.
3 secondary outcomes
Progression-Free Survival (PFS), as Assessed by the Investigator
Time frame: From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)
Overall Response Rate (ORR) During Randomized Phase, as Assessed by the Investigator
Time frame: From randomization until the first documented complete response or partial response (up to approximately 6 years)
Duration of Response (DOR), as Assessed by the Investigator
Time frame: From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Feb 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34225229Schadendorf D, Robert C, Dummer R, Flaherty KT, Tawbi HA, Menzies AM, Banerjee H, Lau M, Long GV. Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers. Eur J Cancer. 2021 Aug;153:234-241. doi: 10.1016/j.ejca.2021.05.005. Epub 2021 Jul 2.
- Derived from this study: PubMed 31166680Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandala M, Haanen JBAG, Lebbe C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019 Aug 15;381(7):626-636. doi: 10.1056/NEJMoa1904059. Epub 2019 Jun 4.
- Derived from this study: PubMed 27864013Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, Davies MA. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016 Dec;17(12):1743-1754. doi: 10.1016/S1470-2045(16)30578-2. Epub 2016 Nov 16.
- Derived from this study: PubMed 26433819Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, Stroyakovskiy D, Drucis K, Grange F, Chiarion-Sileni V, Rutkowski P, Lichinitser M, Levchenko E, Wolter P, Hauschild A, Long GV, Nathan P, Ribas A, Flaherty K, Sun P, Legos JJ, McDowell DO, Mookerjee B, Schadendorf D, Robert C. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015 Oct;16(13):1389-98. doi: 10.1016/S1470-2045(15)00087-X.
- Derived from this study: PubMed 25399551Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. doi: 10.1056/NEJMoa1412690. Epub 2014 Nov 16.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
205 sites in 28 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Dabrafenib, Vemurafenib and Trametinib in people with Melanoma, run by Novartis Pharmaceuticals at 205 sites in 28 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 205 sites in United States, Germany, Canada, France, Australia and 23 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Dec 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall Survival (OS) (time frame: From the date of randomization until date of death due to any cause (up to approximately 6 years)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01597908, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Feb 2021.