GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma

NCT01245062 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: 114267
• Study Type: interventional
• Target: 322
• Locations: 18 countries
• Sites: 102

Brief Summary

This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212 to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV malignant cutaneous melanoma. All subjects must have a BRAF mutation-positive tumour sample. Subjects who have received up to one prior regimen of chemotherapy in the advanced or metastatic melanoma setting will be enrolled into the study. Subjects with any prior BRAF or MEK inhibitor use will be excluded. Approximately 297 subjects will be enrolled with 2:1 randomization (198 subjects into the GSK1120212 arm and 99 subjects into the chemotherapy arm). The primary endpoint for the statistical analysis will be a comparison of progression free survival for subjects receiving GSK1120212 compared to chemotherapy. Subjects who have progression on chemotherapy will be offered the option to receive GSK1120212.

Conditions

Melanoma

Keywords

MEK inhibitor; Cancer; Metastatic Melanoma; BRAF mutant metastatic melanoma; GSK1120212

Outcome Measures

Primary Outcomes (1)

• Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review

  Progression-free survival (PFS) is defined as the time from randomization to the first documented occurrence of disease progression (PD) or death. PFS for investigator-assessed and blinded, independent, central review committee (BRIC)-assessed responses was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer participants improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression is 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. Primary Efficacy Population included all participants with BRAF V600E mutation-positive melanoma without a history of brain metastases.

  Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Secondary Outcomes (16)

• Progression-free Survival in All Participants

  Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

• PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator

  Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

• PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator

  Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

• Overall Survival in All Participants

  Day 1 until death due to any cause (average of 20.3 months)

• Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases

  Day 1 until death due to any cause (average of 20.3 months)

Study Arms (3)

GSK1120212

EXPERIMENTAL

MEK inhibitor

Drug: GSK1120212

Chemotherapy

ACTIVE COMPARATOR

Investigator Choice of DTIC or paclitaxel

Drug: Chemotherapy

Crossover

EXPERIMENTAL

MEK inhibitor after documented progression on Chemotherapy Arm

Drug: GSK1120212

Interventions

GSK1120212 DRUG

MEK inhibitor

Crossover; GSK1120212

Chemotherapy DRUG

Investigator Choice of DTIC or paclitaxel

Chemotherapy

Eligibility Criteria

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

You may qualify if:

• ≥18 years of age
• Stage III unresectable (Stage IIIc) or metastatic (Stage IV) cutaneous melanoma which is also determined to be BRAF V600E/K mutation-positive by the central laboratory
• Received no prior treatment or up to one prior regimen of chemotherapy for advanced or metastatic melanoma. Prior treatment with immunotherapy (with the exception of prior ipilimumab, which is only allowed if given in the adjuvant setting), cytokine therapy, biological or vaccine regimen is permitted. Prior use of sorafenib is allowed
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
• Women of childbearing potential and men with reproductive potential must agree to use effective contraception during the study. Additionally women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
• Adequate screening organ function

You may not qualify if:

• Any prior use of BRAF inhibitors or MEK inhibitors.
• Subjects who have received dacarbazine or paclitaxel prior to randomization will not be eligible to receive the same chemotherapy as study medication (i.e. a subject who received prior dacarbazine cannot receive dacarbazine on this trial and would thus receive paclitaxel if randomized to the control arm)
• History of another malignancy. Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled. Consult GSK Medical Monitor if unsure whether second malignancies meet requirements specified above
• Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed)
• Brain metastases with the following exceptions that are ALL confirmed by the GSK Medical Monitor:
• All known lesions must be previously treated with surgery or stereotactic radiosurgery, and Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size) for ≥90 days prior to randomization (must be documented with two consecutive MRI or CT scans using contrast), and asymptomatic with no corticosteroids requirement for ≥ 30 days prior to randomization, and no enzyme-inducing anticonvulsants for ≥ 30 days prior to randomization
• History or evidence of cardiovascular risk including any of the following:
• QTcB ≥ 480 msec.
• History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for \>30 days prior to randomization are eligible
• History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization.
• History or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association
• History of interstitial lung disease or pneumonitis
• History or current evidence / risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):
• History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).
• Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as:

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (112)

GSK Investigational Site

Tucson, Arizona, 85724-5024, United States

Location

GSK Investigational Site

Fort Myers, Florida, 33916, United States

Location

GSK Investigational Site

Athens, Georgia, 30607, United States

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GSK Investigational Site

Marietta, Georgia, 30060, United States

Location

GSK Investigational Site

Iowa City, Iowa, 52242, United States

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GSK Investigational Site

Metairie, Louisiana, 70006, United States

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GSK Investigational Site

Boston, Massachusetts, 02114, United States

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GSK Investigational Site

Morristown, New Jersey, 07962-1956, United States

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GSK Investigational Site

Columbus, Ohio, 43210, United States

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GSK Investigational Site

Columbia, South Carolina, 29210, United States

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GSK Investigational Site

Chattanooga, Tennessee, 37404, United States

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GSK Investigational Site

Memphis, Tennessee, 38120, United States

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GSK Investigational Site

Nashville, Tennessee, 37203, United States

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GSK Investigational Site

Buenos Aires, C1121ABE, Argentina

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GSK Investigational Site

Garran, Australian Capital Territory, 2606, Australia

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GSK Investigational Site

Port Macquarie, New South Wales, 2444, Australia

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GSK Investigational Site

Waratah, New South Wales, 2300, Australia

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GSK Investigational Site

South Brisbane, Queensland, 4101, Australia

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GSK Investigational Site

Townsville, Queensland, 4810, Australia

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GSK Investigational Site

Woolloongabba, Queensland, 4102, Australia

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GSK Investigational Site

Kurralta Park, South Australia, 5037, Australia

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GSK Investigational Site

Woodville, South Australia, 5011, Australia

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GSK Investigational Site

Heidelberg, Victoria, 3084, Australia

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GSK Investigational Site

Melbourne, Victoria, 3004, Australia

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GSK Investigational Site

Graz, 8036, Austria

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GSK Investigational Site

Vienna, 1090, Austria

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GSK Investigational Site

Brussels, 1200, Belgium

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GSK Investigational Site

Charleroi, 6000, Belgium

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GSK Investigational Site

Ghent, 9000, Belgium

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GSK Investigational Site

Jette, 1090, Belgium

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GSK Investigational Site

Kortrijk, 8500, Belgium

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GSK Investigational Site

Leuven, 3000, Belgium

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GSK Investigational Site

Wilrijk, 2610, Belgium

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GSK Investigational Site

Yvoir, 5530, Belgium

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GSK Investigational Site

Calgary, Alberta, T2N 4N2, Canada

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GSK Investigational Site

Vancouver, British Columbia, V5Z 4E6, Canada

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GSK Investigational Site

Halifax, Nova Scotia, B3H 2Y9, Canada

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GSK Investigational Site

Hamilton, Ontario, L8V 5C2, Canada

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GSK Investigational Site

London, Ontario, N6A 4L6, Canada

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GSK Investigational Site

Oshawa, Ontario, L1G 2B9, Canada

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GSK Investigational Site

Ottawa, Ontario, K1H 8L6, Canada

Location

GSK Investigational Site

Toronto, Ontario, M5G 2M9, Canada

Location

GSK Investigational Site

Montreal, Quebec, H2L 4M1, Canada

Location

GSK Investigational Site

Montreal, Quebec, H2W 1S6, Canada

Location

GSK Investigational Site

Hradec Králové, 500 05, Czechia

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GSK Investigational Site

Ostrava, 708 52, Czechia

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GSK Investigational Site

Prague, 128 08, Czechia

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GSK Investigational Site

Zlín, 76275, Czechia

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GSK Investigational Site

Boulogne-Billancourt, 92100, France

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GSK Investigational Site

Grenoble, 38043, France

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GSK Investigational Site

Montpellier, 34295, France

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GSK Investigational Site

Nantes, 44093, France

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GSK Investigational Site

Paris, 75475, France

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GSK Investigational Site

Pierre-Bénite, 69495, France

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GSK Investigational Site

Rennes, 35042, France

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GSK Investigational Site

Tours, 37044, France

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GSK Investigational Site

Villejuif, 94805, France

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GSK Investigational Site

Heidelberg, Baden-Wurttemberg, 69120, Germany

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GSK Investigational Site

Mannheim, Baden-Wurttemberg, 68167, Germany

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GSK Investigational Site

Tübingen, Baden-Wurttemberg, 72076, Germany

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GSK Investigational Site

Munich, Bavaria, 80804, Germany

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GSK Investigational Site

Würzburg, Bavaria, 97080, Germany

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GSK Investigational Site

Buxtehude, Lower Saxony, 21614, Germany

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GSK Investigational Site

Essen, North Rhine-Westphalia, 45122, Germany

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GSK Investigational Site

Dresden, Saxony, 01307, Germany

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GSK Investigational Site

Lübeck, Schleswig-Holstein, 23538, Germany

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GSK Investigational Site

Berlin, 10117, Germany

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GSK Investigational Site

Athens, 11527, Greece

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GSK Investigational Site

Athens, 185 47, Greece

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GSK Investigational Site

Thessaloniki, 564 29, Greece

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GSK Investigational Site

Milan, Lombardy, 20132, Italy

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GSK Investigational Site

Milan, Lombardy, 20133, Italy

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GSK Investigational Site

Milan, Lombardy, 20141, Italy

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GSK Investigational Site

Pisa, Tuscany, 56126, Italy

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GSK Investigational Site

Christchurch, 8011, New Zealand

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GSK Investigational Site

Dunedin, 9016, New Zealand

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GSK Investigational Site

Newtown, Wellington, 6002, New Zealand

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GSK Investigational Site

Oslo, 0310, Norway

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GSK Investigational Site

Poznan, 61-866, Poland

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GSK Investigational Site

Warsaw, 02-781, Poland

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GSK Investigational Site

Warsaw, 04-125, Poland

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GSK Investigational Site

Chelyabinsk, 454087, Russia

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GSK Investigational Site

Magnitogorsk, 455001, Russia

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GSK Investigational Site

Moscow, 115478, Russia

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GSK Investigational Site

Saint Petersburg, 197758, Russia

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GSK Investigational Site

Gothenburg, SE-413 45, Sweden

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GSK Investigational Site

Linköping, SE-581 85, Sweden

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GSK Investigational Site

Lund, SE-221 85, Sweden

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GSK Investigational Site

Stockholm, SE-171 76, Sweden

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GSK Investigational Site

Uppsala, SE-751 85, Sweden

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GSK Investigational Site

Zurich, 8091, Switzerland

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GSK Investigational Site

Dnipro, 49102, Ukraine

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GSK Investigational Site

Kharkiv, 61070, Ukraine

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GSK Investigational Site

Kyiv, 03022, Ukraine

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GSK Investigational Site

Kyiv, 03115, Ukraine

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GSK Investigational Site

Lviv, 79031, Ukraine

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GSK Investigational Site

Sumy, 40005, Ukraine

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GSK Investigational Site

Sympheropol, 95023, Ukraine

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GSK Investigational Site

Ternopil, 46023, Ukraine

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GSK Investigational Site

Uzhhorod, 88017, Ukraine

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GSK Investigational Site

Cambridge, Cambridgeshire, CB2 2QQ, United Kingdom

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GSK Investigational Site

Northwood, Middlesex, HA6 2RN, United Kingdom

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GSK Investigational Site

Sutton, Surrey, SM2 5PT, United Kingdom

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GSK Investigational Site

Aberdeen, AB25 2ZN, United Kingdom

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GSK Investigational Site

Birmingham, B15 2TH, United Kingdom

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GSK Investigational Site

Chelmsford, CM1 7ET, United Kingdom

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GSK Investigational Site

Leeds, LS9 7TF, United Kingdom

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GSK Investigational Site

London, SW3 6JJ, United Kingdom

Location

GSK Investigational Site

London, W1G 6AD, United Kingdom

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GSK Investigational Site

Manchester, M20 4BX, United Kingdom

Location

GSK Investigational Site

Oxford, OX3 7LJ, United Kingdom

Location

GSK Investigational Site

Southampton, SO16 6YD, United Kingdom

Location

Related Publications (6)

• KT Flaherty, C Robert, P Hersey, P Nathan, C Garbe, M Milhem, L Demidov, J Hassel, P Rutkowski, P Mohr, R Dummer, U Trefzer, JMG Larkin, J Utikal, B Dreno, M Nyakas, MR Middleton, JC Becker, M Casey, LJ Sherman, FS Wu, D Ouellet, AM Martin, K Patel, & D S. MEK inhibition improves survival in Melanoma with activating BRAF Mutations. [N Engl J Med]. 2012;367:107-14.

  BACKGROUND

• Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. doi: 10.1056/NEJMoa1203421. Epub 2012 Jun 4.

  PMID: 22663011 RESULT

• Robert C, Flaherty K, Nathan P, Hersey P, Garbe C, Milhem M, Demidov L, Mohr P, Hassel JC, Rutkowski P, Dummer R, Utikal J, Kiecker F, Larkin J, D'Amelio A Jr, Mookerjee B, Schadendorf D. Five-year outcomes from a phase 3 METRIC study in patients with BRAF V600 E/K-mutant advanced or metastatic melanoma. Eur J Cancer. 2019 Mar;109:61-69. doi: 10.1016/j.ejca.2018.12.015. Epub 2019 Jan 25.

  PMID: 30690294 DERIVED

• Latimer NR, Bell H, Abrams KR, Amonkar MM, Casey M. Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy. Cancer Med. 2016 May;5(5):806-15. doi: 10.1002/cam4.643. Epub 2016 Jan 27.

  PMID: 27172483 DERIVED

• Santiago-Walker A, Gagnon R, Mazumdar J, Casey M, Long GV, Schadendorf D, Flaherty K, Kefford R, Hauschild A, Hwu P, Haney P, O'Hagan A, Carver J, Goodman V, Legos J, Martin AM. Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials. Clin Cancer Res. 2016 Feb 1;22(3):567-74. doi: 10.1158/1078-0432.CCR-15-0321. Epub 2015 Oct 7.

  PMID: 26446943 DERIVED

• Schadendorf D, Amonkar MM, Milhem M, Grotzinger K, Demidov LV, Rutkowski P, Garbe C, Dummer R, Hassel JC, Wolter P, Mohr P, Trefzer U, Lefeuvre-Plesse C, Rutten A, Steven N, Ullenhag G, Sherman L, Wu FS, Patel K, Casey M, Robert C. Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study. Ann Oncol. 2014 Mar;25(3):700-706. doi: 10.1093/annonc/mdt580. Epub 2014 Feb 6.

  PMID: 24504441 DERIVED

MeSH Terms

Conditions

Melanoma; Neoplasms

Interventions

trametinib; Drug Therapy

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Therapeutics

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  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: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2010
• First Posted: November 22, 2010
• Study Start: November 22, 2010
• Primary Completion: October 26, 2011
• Study Completion: December 16, 2016
• Last Updated: April 5, 2018
• Results First Posted: March 15, 2013

Record last verified: 2018-01

Locations

AR (1); FR (9); GB (12); NO (1); NZ (3); IT (4); CA (10); CZ (4); CH (1); BE (8); AU (2); SE (5); UA (9); GR (3); RU (4); PL (3); DE (10); US (13)