A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma

NCT01584648 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: 1153062011-006087-49CDRB436B2301
• Study Type: interventional
• Target: 423
• Locations: 14 countries
• Sites: 121

Brief 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). 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.

Conditions

Melanoma

Keywords

Randomized study; combination therapy; BRAF inhibitor; GSK1120212; BRAF V600E/K mutation-positive cutaneous melanoma; trametinib; GSK2118436; MEK inhibitor; Phase III; dabrafenib

Outcome Measures

Primary Outcomes (1)

• 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.

  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)

  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

  From randomization until the first documented complete response or partial response (up to approximately 6 years)

• Duration of Response (DoR)

  From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)

• Trametinib Pharmacokinetic Concentrations

  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

  Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)

Study Arms (2)

Dabrafenib + Trametinib

EXPERIMENTAL

Dabrafenib and Trametinib combination

Drug: Dabrafenib; Drug: Trametinib

Dabrafenib + Placebo

ACTIVE COMPARATOR

Dabrafenib and Trametinib placebo

Drug: Dabrafenib; Drug: Trametinib placebo

Interventions

Dabrafenib DRUG

Dabrafenib 150 mg twice daily

Also known as: GSK2118436

Dabrafenib + Placebo; Dabrafenib + Trametinib

Trametinib DRUG

Trametinib 2 mg once daily

Also known as: GSK1120212

Dabrafenib + Trametinib

Trametinib placebo DRUG

Dabrafenib 150 mg twice daily and trametinib placebo

Also known as: Placebo

Dabrafenib + Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (121)

Novartis Investigative Site

Scottsdale, Arizona, 85258, United States

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Novartis Investigative Site

Tucson, Arizona, 85719, United States

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Novartis Investigative Site

Los Angeles, California, 90024, United States

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Novartis Investigative Site

Fort Myers, Florida, 33916, United States

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Novartis Investigative Site

St. Petersburg, Florida, 33705, United States

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Novartis Investigative Site

Tampa, Florida, 33612, United States

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Novartis Investigative Site

West Palm Beach, Florida, 33401, United States

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Novartis Investigative Site

Peoria, Illinois, 61615-7822, United States

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Novartis Investigative Site

Indianapolis, Indiana, 46202, United States

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Novartis Investigative Site

Boston, Massachusetts, 02114, United States

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Novartis Investigative Site

Boston, Massachusetts, 02215, United States

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New York, New York, 10065, United States

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Cincinnati, Ohio, 45242, United States

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Philadelphia, Pennsylvania, 19104, United States

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Columbia, South Carolina, 29210, United States

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Chattanooga, Tennessee, 37404, United States

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Nashville, Tennessee, 37203, United States

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Novartis Investigative Site

Fort Worth, Texas, 76104, United States

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Novartis Investigative Site

Richmond, Virginia, 23230, United States

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Novartis Investigative Site

CABA, Buenos Aires, C1425DTG, Argentina

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Novartis Investigative Site

Capital Federal, Buenos Aires, C1426ANZ, Argentina

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Novartis Investigative Site

Ciudad Autonoma de Buenos Aires, Buenos Aires, C1050AAK, Argentina

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Novartis Investigative Site

North Sydney, New South Wales, 2060, Australia

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Novartis Investigative Site

Westmead, New South Wales, 2145, Australia

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Woolloongabba, Queensland, 4102, Australia

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Novartis Investigative Site

Adelaide, South Australia, 5000, Australia

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Heidelberg, Victoria, 3084, Australia

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Nedlands, Western Australia, 6009, Australia

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Edmonton, Alberta, T6G 1Z2, Canada

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Hamilton, Ontario, L8V 5C2, Canada

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London, Ontario, N6A 4L6, Canada

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Toronto, Ontario, M5G 2M9, Canada

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Novartis Investigative Site

Montreal, Quebec, H2W 1S6, Canada

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Montreal, Quebec, H3A 1A1, Canada

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Novartis Investigative Site

Bordeaux, 33075, France

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Boulogne-Billancourt, 92100, France

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Lyon, 69373, France

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Marseille, 13385, France

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Novartis Investigative Site

Paris, 75006, France

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Novartis Investigative Site

Paris, 75018, France

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Paris, 75475, France

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Toulouse, 31052, France

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Novartis Investigative Site

Vandœuvre-lès-Nancy, 54511, France

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Heidelberg, Baden-Wurttemberg, 69120, Germany

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Heilbronn, Baden-Wurttemberg, 74078, Germany

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Mannheim, Baden-Wurttemberg, 68167, Germany

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Tübingen, Baden-Wurttemberg, 72076, Germany

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Ulm, Baden-Wurttemberg, 89081, Germany

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Augsburg, Bavaria, 86179, Germany

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Erlangen, Bavaria, 91054, Germany

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Munich, Bavaria, 80337, Germany

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Munich, Bavaria, 80804, Germany

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Munich, Bavaria, 81675, Germany

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Nuremberg, Bavaria, 90419, Germany

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Regensburg, Bavaria, 93053, Germany

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Würzburg, Bavaria, 97080, Germany

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Darmstadt, Hesse, 64283, Germany

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Marburg, Hesse, 35033, Germany

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Buxtehude, Lower Saxony, 21614, Germany

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Hanover, Lower Saxony, 30625, Germany

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Bonn, North Rhine-Westphalia, 53127, Germany

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Cologne, North Rhine-Westphalia, 50937, Germany

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Essen, North Rhine-Westphalia, 45122, Germany

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Mainz, Rhineland-Palatinate, 55131, Germany

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Homburg, Saarland, 66421, Germany

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Dresden, Saxony, 01307, Germany

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Leipzig, Saxony, 04103, Germany

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Magdeburg, Saxony-Anhalt, 39120, Germany

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Kiel, Schleswig-Holstein, 24105, Germany

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Lübeck, Schleswig-Holstein, 23538, Germany

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Erfurt, Thuringia, 99089, Germany

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Gera, Thuringia, 07548, Germany

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Jena, Thuringia, 07740, Germany

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Berlin, 10117, Germany

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Athens, 11527, Greece

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N. Faliro, 185 47, Greece

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Thessaloniki, 564 29, Greece

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Rome, Lazio, 00144, Italy

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Rome, Lazio, 00167, Italy

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Genoa, Liguria, 16132, Italy

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Bergamo, Lombardy, 24127, Italy

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Milan, Lombardy, 20133, Italy

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Milan, Lombardy, 20141, Italy

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Novartis Investigative Site

Candiolo (TO), Piedmont, 10060, Italy

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Padua, Veneto, 35128, Italy

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Amsterdam, 1066 CX, Netherlands

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Amsterdam, 1081 HV, Netherlands

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Zwolle, 8025 AB, Netherlands

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Kazan', 420029, Russia

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Moscow, 143423, Russia

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Saint Petersburg, 197758, Russia

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Stavropol, 355047, Russia

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Barcelona, 08035, Spain

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Novartis Investigative Site

Barcelona, 08036, Spain

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Novartis Investigative Site

Madrid, 28034, Spain

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Novartis Investigative Site

Madrid, 28041, Spain

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Novartis Investigative Site

Madrid, 28046, Spain

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Novartis Investigative Site

Pamplona, 31008, Spain

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Novartis Investigative Site

Valencia, 46010, Spain

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Novartis Investigative Site

Gothenburg, SE-413 45, Sweden

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Novartis Investigative Site

Lund, SE-221 85, Sweden

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Stockholm, SE-171 76, Sweden

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Uppsala, SE-751 85, Sweden

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Dnipropetrovsk, 49100, Ukraine

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Dnipropetrovsk, 49102, Ukraine

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Donetsk, 83092, Ukraine

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Novartis Investigative Site

Khmelnytskyi, 29009, Ukraine

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Novartis Investigative Site

Kyiv, 03022, Ukraine

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Lviv, 79031, Ukraine

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Sumy, 40005, Ukraine

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Northwood, Middlesex, HA6 2RN, United Kingdom

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Sutton, Surrey, SM2 5PT, United Kingdom

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Aberdeen, AB25 2ZN, United Kingdom

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Bebington, CH63 4JY, United Kingdom

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Edgbaston, Birmingham, B15 2TH, United Kingdom

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Novartis Investigative Site

Leeds, LS9 7TF, United Kingdom

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London, SW3 6JJ, United Kingdom

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Newcastle upon Tyne, NE7 7DN, United Kingdom

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Nottingham, NG5 1PB, United Kingdom

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Oxford, OX3 7LJ, United Kingdom

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Novartis Investigative Site

Preston, PR2 9HT, United Kingdom

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Related Publications (8)

• 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.

  PMID: 34225229 DERIVED

• Syeda 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.

  PMID: 33587894 DERIVED

• Robert 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.

  PMID: 31166680 DERIVED

• Long 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.

  PMID: 27864013 DERIVED

• Long 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.

  PMID: 26037941 DERIVED

• Schadendorf 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.

  PMID: 25794603 DERIVED

• Menzies 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.

  PMID: 25411413 DERIVED

• Long 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.

  PMID: 25265492 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 23, 2012
• First Posted: April 25, 2012
• Study Start: May 4, 2012
• Primary Completion: August 26, 2013
• Study Completion: February 28, 2019
• Last Updated: February 17, 2021
• Results First Posted: August 15, 2014

Record last verified: 2021-02

Locations

DE (31); NL (3); US (19); RU (4); SE (4); GB (11); IT (8); UA (7); CA (6); GR (3); ES (7); FR (9); AU (6); AR (3)