MelanomaPhase 3NCT01584648
A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma
A Phase 3 study testing Dabrafenib and Trametinib in people with Melanoma, run by Novartis Pharmaceuticals at 121 sites in 14 countries.
Trial summary
This was a two-arm, double-blinded, randomized, Phase III study comparing dabrafenib and trametinib combination therapy to dabrafenib administered with a placebo (dabrafenib monotherapy). 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 and Trametinib
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 423 participants
- Where
- 121 sitesin 14 countries
- Study dates
- 4 May 2012to 28 Feb 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
- Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). The assay will be conducted by a central reference laboratory. Subjects with ocular or mucosal melanoma are not eligible.
- The subject must have a radiologically measurable tumor
- The subject is able to carry out daily life activities without significant difficulty (ECOG performance status score of 0 or 1).
- Able to swallow and retain oral medication
- Sexually active subjects must use acceptable methods of contraception during the course of the study
- Adequate organ system function and blood counts
Who cannot join
- Prior treatment with a BRAF or a MEK inhibitor
- Prior systemic anti-cancer treatment for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed. (Note: Ipilimumab treatment must end at least 8 weeks prior to randomization.)
- The subject has received major surgery or certain tyes of cancer therapy with 21 days of starting treatment
- Current use of prohibited medication listed in the protocol
- Left ventricular ejection fraction less than the lower limit of normal
- Uncontrolled blood pressurl
Show all 9Show fewer
- History or current evidence of retinal vein occlusion or central serous retinopathy
- Brain metastases unless previously treated with surgery or stereotactic radiosurgery and the disease has been stable for at least 12 weeks
- The subject is pregnant or nursing
Trial locations and contacts
121 sites in 14 countries.
121 sites in 14 countries
Germany31 sites
Novartis Investigative Site
Augsburg, Bavaria, 86179
Novartis Investigative Site
Berlin, 10117
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
Darmstadt, Hesse, 64283
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
Homburg, Saarland, 66421
Novartis Investigative Site
Jena, Thuringia, 07740
Novartis Investigative Site
Kiel, Schleswig-Holstein, 24105
Novartis Investigative Site
Leipzig, Saxony, 04103
Novartis Investigative Site
Lübeck, Schleswig-Holstein, 23538
Novartis Investigative Site
Magdeburg, Saxony-Anhalt, 39120
Novartis Investigative Site
Mainz, Rhineland-Palatinate, 55131
Novartis Investigative Site
Mannheim, Baden-Wurttemberg, 68167
Novartis Investigative Site
Marburg, Hesse, 35033
Novartis Investigative Site
Munich, Bavaria, 80337
Novartis Investigative Site
Munich, Bavaria, 80804
Novartis Investigative Site
Munich, Bavaria, 81675
Novartis Investigative Site
Nuremberg, Bavaria, 90419
Novartis Investigative Site
Regensburg, Bavaria, 93053
Novartis Investigative Site
Tübingen, Baden-Wurttemberg, 72076
Novartis Investigative Site
Ulm, Baden-Wurttemberg, 89081
Novartis Investigative Site
Würzburg, Bavaria, 97080
United States19 sites
Novartis Investigative Site
Boston, Massachusetts, 02114
Novartis Investigative Site
Boston, Massachusetts, 02215
Novartis Investigative Site
Chattanooga, Tennessee, 37404
Novartis Investigative Site
Cincinnati, Ohio, 45242
Novartis Investigative Site
Columbia, South Carolina, 29210
Novartis Investigative Site
Fort Myers, Florida, 33916
Novartis Investigative Site
Fort Worth, Texas, 76104
Novartis Investigative Site
Indianapolis, Indiana, 46202
Novartis Investigative Site
Los Angeles, California, 90024
Novartis Investigative Site
Nashville, Tennessee, 37203
Novartis Investigative Site
New York, New York, 10065
Novartis Investigative Site
Peoria, Illinois, 61615-7822
Novartis Investigative Site
Philadelphia, Pennsylvania, 19104
Novartis Investigative Site
Richmond, Virginia, 23230
Novartis Investigative Site
Scottsdale, Arizona, 85258
Novartis Investigative Site
St. Petersburg, Florida, 33705
Novartis Investigative Site
Tampa, Florida, 33612
Novartis Investigative Site
Tucson, Arizona, 85719
Novartis Investigative Site
West Palm Beach, Florida, 33401
United Kingdom11 sites
Novartis Investigative Site
Aberdeen, AB25 2ZN
Novartis Investigative Site
Bebington, CH63 4JY
Novartis Investigative Site
Edgbaston, Birmingham, B15 2TH
Novartis Investigative Site
Leeds, LS9 7TF
Novartis Investigative Site
London, SW3 6JJ
Novartis Investigative Site
Newcastle upon Tyne, NE7 7DN
Novartis Investigative Site
Northwood, Middlesex, HA6 2RN
Novartis Investigative Site
Nottingham, NG5 1PB
Novartis Investigative Site
Oxford, OX3 7LJ
Novartis Investigative Site
Preston, PR2 9HT
Novartis Investigative Site
Sutton, Surrey, SM2 5PT
France9 sites
Novartis Investigative Site
Bordeaux, 33075
Novartis Investigative Site
Boulogne-Billancourt, 92100
Novartis Investigative Site
Lyon, 69373
Novartis Investigative Site
Marseille, 13385
Novartis Investigative Site
Paris, 75006
Novartis Investigative Site
Paris, 75018
Novartis Investigative Site
Paris, 75475
Novartis Investigative Site
Toulouse, 31052
Novartis Investigative Site
Vandœuvre-lès-Nancy, 54511
Italy8 sites
Novartis Investigative Site
Bergamo, Lombardy, 24127
Novartis Investigative Site
Candiolo (TO), Piedmont, 10060
Novartis Investigative Site
Genoa, Liguria, 16132
Novartis Investigative Site
Milan, Lombardy, 20133
Novartis Investigative Site
Milan, Lombardy, 20141
Novartis Investigative Site
Padova, Veneto, 35128
Novartis Investigative Site
Rome, Lazio, 00144
Novartis Investigative Site
Rome, Lazio, 00167
Spain7 sites
Novartis Investigative Site
Barcelona, 08035
Novartis Investigative Site
Barcelona, 08036
Novartis Investigative Site
Madrid, 28034
Novartis Investigative Site
Madrid, 28041
Novartis Investigative Site
Madrid, 28046
Novartis Investigative Site
Pamplona, 31008
Novartis Investigative Site
Valencia, 46010
Ukraine7 sites
Novartis Investigative Site
Dnipropetrovsk, 49100
Novartis Investigative Site
Dnipropetrovsk, 49102
Novartis Investigative Site
Donetsk, 83092
Novartis Investigative Site
Khmelnytskyi, 29009
Novartis Investigative Site
Kyiv, 03022
Novartis Investigative Site
Lviv, 79031
Novartis Investigative Site
Sumy, 40005
Australia6 sites
Novartis Investigative Site
Adelaide, South Australia, 5000
Novartis Investigative Site
Heidelberg, Victoria, 3084
Novartis Investigative Site
Nedlands, Western Australia, 6009
Novartis Investigative Site
North Sydney, New South Wales, 2060
Novartis Investigative Site
Westmead, New South Wales, 2145
Novartis Investigative Site
Woolloongabba, Queensland, 4102
Canada6 sites
Novartis Investigative Site
Edmonton, Alberta, T6G 1Z2
Novartis Investigative Site
Hamilton, Ontario, L8V 5C2
Novartis Investigative Site
London, Ontario, N6A 4L6
Novartis Investigative Site
Montreal, Quebec, H2W 1S6
Novartis Investigative Site
Montreal, Quebec, H3A 1A1
Novartis Investigative Site
Toronto, Ontario, M5G 2M9
Russia4 sites
Novartis Investigative Site
Kazan', 420029
Novartis Investigative Site
Moscow, 143423
Novartis Investigative Site
Saint Petersburg, 197758
Novartis Investigative Site
Stavropol, 355047
Sweden4 sites
Novartis Investigative Site
Gothenburg, SE-413 45
Novartis Investigative Site
Lund, SE-221 85
Novartis Investigative Site
Stockholm, SE-171 76
Novartis Investigative Site
Uppsala, SE-751 85
Argentina3 sites
Novartis Investigative Site
CABA, Buenos Aires, C1425DTG
Novartis Investigative Site
Capital Federal, Buenos Aires, C1426ANZ
Novartis Investigative Site
Ciudad Autonoma de Buenos Aires, Buenos Aires, C1050AAK
Greece3 sites
Novartis Investigative Site
Athens, 11527
Novartis Investigative Site
N. Faliro, 185 47
Novartis Investigative Site
Thessaloniki, 564 29
Netherlands3 sites
Novartis Investigative Site
Amsterdam, 1066 CX
Novartis Investigative Site
Amsterdam, 1081 HV
Novartis Investigative Site
Zwolle, 8025 AB
About this study
Official title: A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy in Subjects With Unresectable (Stage IIIC) or Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma
This was a two-arm, double-blinded, randomized, Phase III study comparing dabrafenib and trametinib combination therapy to dabrafenib administered with a placebo (dabrafenib monotherapy). Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive were screened for eligibility. 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. Subjects were stratified according to the baseline lactate dehydrogenase level and BRAF genotype.
Read the detailed description
Dabrafenib and trametinib was administered orally at their recommended monotherapy doses of 150 mg b.i.d and 2 mg q.d., respectively. Subjects in the combination therapy arm received both agents; subjects in the dabrafenib monotherapy arm received dabrafenib and placebo. Treatment was continued in both arms until disease progression, death, unacceptable toxicity, or withdrawal of consent.
After treatment discontinuation, subjects were followed for survival and disease progression as applicable to collect data for the secondary objective of overall survival (OS).
Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
- Conditions
- Melanoma
- Being tested
- Dabrafenib, Trametinib, Trametinib placebo
- Keywords
- Randomized study, combination therapy, BRAF inhibitor, GSK1120212, BRAF V600E/K mutation-positive cutaneous melanoma, trametinib, GSK2118436, MEK inhibitor, Phase III, dabrafenib
- Medical subject headings
- Melanoma
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
TrametinibDrug
Also called GSK1120212
Trametinib 2 mg once daily
Trametinib placeboDrug
Also called Placebo
Dabrafenib 150 mg twice daily and trametinib placebo
| Study group | Role | What they receive |
|---|---|---|
| Dabrafenib + Trametinib | Experimental | Dabrafenib and Trametinib combination Receives: Drug: Dabrafenib; Drug: Trametinib |
| Dabrafenib + Placebo | Active comparator | Dabrafenib and Trametinib placebo Receives: Drug: Dabrafenib; Drug: Trametinib placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression-Free Survival (PFS) as Assessed by the Investigator
PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. The appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation, was also included as PD. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not have documented progression or death, PFS was censored at the date of the last adequate assessment.
Measured: From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)
Secondary outcomes (6)
Overall Survival (OS)
OS is defined as the interval of time between the date of randomization and the date of death due to any cause. For the participants who did not die, overall survival 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)
Objective Response Rate (ORR) as Assessed by the Investigator
ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR). A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm). Only descriptive analysis performed.
Measured: From randomization until the first documented complete response or partial response (up to approximately 6 years)
Duration of Response (DoR)
Duration of response is defined as the time from the first documented complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm) until disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5mm or the appearance of one or more new lesions, or the worsening of non target lesions significant enough to require study treatment discontinuation. PD was based on the radiological evidence by investigator. Only descriptive analysis performed.
Measured: From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)
Trametinib Pharmacokinetic Concentrations
Blood samples were collected for Pharmacokinetic (PK) analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Only descriptive analysis performed.
Measured: Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)
Dabrafenib and Dabrafenib Metabolites (Hydroxy-, Carboxy- and Desmethyl-Dabrafenib) Concentrations
Blood samples were collected for PK analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Plasma concentrations of Dabrafenib (GSK2118436) and its metabolites (Hydroxy-Dabrafenib (GSK2285403), Carboxy-Dabrafenib (GSK2298683), and Desmethyl-Dabrafenib (GSK2167542)) were determined using the currently approved analytical methodology. Only descriptive analysis performed.
Measured: Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)
Number of Participants With Adverse Events and Serious Adverse Events
Analysis of absolute and relative frequencies for Adverse Event (AE) and Serious Adverse Event (SAE) by primary System Organ Class (SOC) to characterize the safety of dabrafenib and trametinib combination therapy through the monitoring of relevant clinical and laboratory safety parameters. In addition, new malignancies and AEs possibly related to study treatment were collected even if they occurred more than 30 days post-treatment. Only descriptive analysis performed.
Measured: From the time the first dose of study treatment administered until 30 days after discontinuation of study treatment (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 posted25 Apr 2012 (estimated)
- Study start4 May 2012
- Primary completion26 Aug 2013
- Study completion28 Feb 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 (8)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
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 423 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
- NCT01584648
- Sponsor's protocol ID
- 115306
- Other IDs
- 2011-006087-49, CDRB436B2301
- Status last verified
- Feb 2021
- First submitted
- 23 Apr 2012
- Last updated
- 17 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
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 34225229Syeda MM, Wiggins JM, Corless BC, Long GV, Flaherty KT, Schadendorf D, Nathan PD, Robert C, Ribas A, Davies MA, Grob JJ, Gasal E, Squires M, Marker M, Garrett J, Brase JC, Polsky D. Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study. Lancet Oncol. 2021 Mar;22(3):370-380. doi: 10.1016/S1470-2045(20)30726-9. Epub 2021 Feb 12.
PubMed 33587894Robert 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 27864013Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51. doi: 10.1016/S0140-6736(15)60898-4. Epub 2015 May 31.
PubMed 26037941Schadendorf D, Amonkar MM, Stroyakovskiy D, Levchenko E, Gogas H, de Braud F, Grob JJ, Bondarenko I, Garbe C, Lebbe C, Larkin J, Chiarion-Sileni V, Millward M, Arance A, Mandala M, Flaherty KT, Nathan P, Ribas A, Robert C, Casey M, DeMarini DJ, Irani JG, Aktan G, Long GV. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. Eur J Cancer. 2015 May;51(7):833-40. doi: 10.1016/j.ejca.2015.03.004. Epub 2015 Mar 17.
PubMed 25794603Menzies AM, Ashworth MT, Swann S, Kefford RF, Flaherty K, Weber J, Infante JR, Kim KB, Gonzalez R, Hamid O, Schuchter L, Cebon J, Sosman JA, Little S, Sun P, Aktan G, Ouellet D, Jin F, Long GV, Daud A. Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial. Ann Oncol. 2015 Feb;26(2):415-21. doi: 10.1093/annonc/mdu529. Epub 2014 Nov 18.
PubMed 25411413Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88. doi: 10.1056/NEJMoa1406037. Epub 2014 Sep 29.
PubMed 25265492
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy in Subjects With Unresectable (Stage IIIC) or Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma
- ClinicalTrials.gov ID
- NCT01584648
- Acronym / sponsor ID
- 115306
- Conditions
- Melanoma
- Keywords
- Randomized study, combination therapy, BRAF inhibitor, GSK1120212, BRAF V600E/K mutation-positive cutaneous melanoma, trametinib, GSK2118436, MEK inhibitor
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 423 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 4 May 2012 (actual)
- Primary completion
- 26 Aug 2013 (actual)
- Study completion
- 28 Feb 2019 (actual)
- First posted
- 25 Apr 2012 (estimated)
- Results
- Posted 15 Aug 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, double-blinded, randomized, Phase III study comparing dabrafenib and trametinib combination therapy to dabrafenib administered with a placebo (dabrafenib monotherapy). Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive were screened for eligibility. 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. Subjects were stratified according to the baseline lactate dehydrogenase level and BRAF genotype.
Detailed description
Dabrafenib and trametinib was administered orally at their recommended monotherapy doses of 150 mg b.i.d and 2 mg q.d., respectively. Subjects in the combination therapy arm received both agents; subjects in the dabrafenib monotherapy arm received dabrafenib and placebo. Treatment was continued in both arms until disease progression, death, unacceptable toxicity, or withdrawal of consent.
After treatment discontinuation, subjects were followed for survival and disease progression as applicable to collect data for the secondary objective of overall survival (OS).
Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dabrafenib + Trametinib | Experimental | Drug: Dabrafenib, Drug: TrametinibDabrafenib and Trametinib combination |
| Dabrafenib + Placebo | Active comparator | Drug: Dabrafenib, Drug: Trametinib placeboDabrafenib and Trametinib placebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). The assay will be conducted by a central reference laboratory. Subjects with ocular or mucosal melanoma are not eligible.
- The subject must have a radiologically measurable tumor
- The subject is able to carry out daily life activities without significant difficulty (ECOG performance status score of 0 or 1).
- Able to swallow and retain oral medication
- Sexually active subjects must use acceptable methods of contraception during the course of the study
Key exclusion criteria (9 listed)
- Prior treatment with a BRAF or a MEK inhibitor
- Prior systemic anti-cancer treatment for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed. (Note: Ipilimumab treatment must end at least 8 weeks prior to randomization.)
- The subject has received major surgery or certain tyes of cancer therapy with 21 days of starting treatment
- Current use of prohibited medication listed in the protocol
- Left ventricular ejection fraction less than the lower limit of normal
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 | Drug | Dabrafenib + Placebo, Dabrafenib + Trametinib |
| TrametinibAlso: GSK1120212Trametinib 2 mg once daily | Drug | Dabrafenib + Trametinib |
| Trametinib placeboAlso: PlaceboDabrafenib 150 mg twice daily and trametinib placebo | Drug | Dabrafenib + Placebo |
Primary outcome
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)
PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. The appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation, was also included as PD. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not have documented progression or death, PFS was censored at the date of the last adequate assessment.
6 secondary outcomes
Overall Survival (OS)
Time frame: From the date of randomization until date of death due to any cause (up to approximately 6 years)
Objective Response Rate (ORR) 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)
Time frame: From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)
Trametinib Pharmacokinetic Concentrations
Time frame: Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)
Dabrafenib and Dabrafenib Metabolites (Hydroxy-, Carboxy- and Desmethyl-Dabrafenib) Concentrations
Time frame: Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)
Number of Participants With Adverse Events and Serious Adverse Events
Time frame: From the time the first dose of study treatment administered until 30 days after discontinuation of study treatment (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 17 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 33587894Syeda MM, Wiggins JM, Corless BC, Long GV, Flaherty KT, Schadendorf D, Nathan PD, Robert C, Ribas A, Davies MA, Grob JJ, Gasal E, Squires M, Marker M, Garrett J, Brase JC, Polsky D. Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study. Lancet Oncol. 2021 Mar;22(3):370-380. doi: 10.1016/S1470-2045(20)30726-9. Epub 2021 Feb 12.
- 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 26037941Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51. doi: 10.1016/S0140-6736(15)60898-4. Epub 2015 May 31.
- Derived from this study: PubMed 25794603Schadendorf D, Amonkar MM, Stroyakovskiy D, Levchenko E, Gogas H, de Braud F, Grob JJ, Bondarenko I, Garbe C, Lebbe C, Larkin J, Chiarion-Sileni V, Millward M, Arance A, Mandala M, Flaherty KT, Nathan P, Ribas A, Robert C, Casey M, DeMarini DJ, Irani JG, Aktan G, Long GV. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. Eur J Cancer. 2015 May;51(7):833-40. doi: 10.1016/j.ejca.2015.03.004. Epub 2015 Mar 17.
- Derived from this study: PubMed 25411413Menzies AM, Ashworth MT, Swann S, Kefford RF, Flaherty K, Weber J, Infante JR, Kim KB, Gonzalez R, Hamid O, Schuchter L, Cebon J, Sosman JA, Little S, Sun P, Aktan G, Ouellet D, Jin F, Long GV, Daud A. Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial. Ann Oncol. 2015 Feb;26(2):415-21. doi: 10.1093/annonc/mdu529. Epub 2014 Nov 18.
- Derived from this study: PubMed 25265492Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88. doi: 10.1056/NEJMoa1406037. Epub 2014 Sep 29.
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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
121 sites in 14 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Dabrafenib and Trametinib in people with Melanoma, run by Novartis Pharmaceuticals at 121 sites in 14 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 9 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 17 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 121 sites in Germany, United States, United Kingdom, France, Italy and 9 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 15 Aug 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?
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)). 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 NCT01584648, which also lists 8 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 17 Feb 2021.