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

NCT ID: NCT01245062

Last Updated: 2018-04-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 322 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-11-22
• Study Completion Date: 2016-12-16

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

GSK1120212

MEK inhibitor

Group Type: EXPERIMENTAL

GSK1120212

Intervention Type: DRUG

MEK inhibitor

Chemotherapy

Investigator Choice of DTIC or paclitaxel

Group Type: ACTIVE_COMPARATOR

Chemotherapy

Intervention Type: DRUG

Investigator Choice of DTIC or paclitaxel

Crossover

MEK inhibitor after documented progression on Chemotherapy Arm

Group Type: EXPERIMENTAL

GSK1120212

Intervention Type: DRUG

MEK inhibitor

Interventions

GSK1120212

MEK inhibitor

Intervention Type: DRUG

Chemotherapy

Investigator Choice of DTIC or paclitaxel

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• ≥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

Exclusion Criteria

• 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:
• Evidence of new optic disc cupping.
• Intraocular pressure > 21 mm Hg as measured by tonography

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Tucson, Arizona, United States

GSK Investigational Site

Fort Myers, Florida, United States

GSK Investigational Site

Athens, Georgia, United States

GSK Investigational Site

Marietta, Georgia, United States

GSK Investigational Site

Iowa City, Iowa, United States

GSK Investigational Site

Metairie, Louisiana, United States

GSK Investigational Site

Boston, Massachusetts, United States

GSK Investigational Site

Morristown, New Jersey, United States

GSK Investigational Site

Columbus, Ohio, United States

GSK Investigational Site

Columbia, South Carolina, United States

GSK Investigational Site

Chattanooga, Tennessee, United States

GSK Investigational Site

Memphis, Tennessee, United States

GSK Investigational Site

Nashville, Tennessee, United States

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Garran, Australian Capital Territory, Australia

GSK Investigational Site

Port Macquarie, New South Wales, Australia

GSK Investigational Site

Waratah, New South Wales, Australia

GSK Investigational Site

South Brisbane, Queensland, Australia

GSK Investigational Site

Townsville, Queensland, Australia

GSK Investigational Site

Woolloongabba, Queensland, Australia

GSK Investigational Site

Kurralta Park, South Australia, Australia

GSK Investigational Site

Woodville, South Australia, Australia

GSK Investigational Site

Heidelberg, Victoria, Australia

GSK Investigational Site

Melbourne, Victoria, Australia

GSK Investigational Site

Graz, , Austria

GSK Investigational Site

Vienna, , Austria

GSK Investigational Site

Brussels, , Belgium

GSK Investigational Site

Charleroi, , Belgium

GSK Investigational Site

Ghent, , Belgium

GSK Investigational Site

Jette, , Belgium

GSK Investigational Site

Kortrijk, , Belgium

GSK Investigational Site

Leuven, , Belgium

GSK Investigational Site

Wilrijk, , Belgium

GSK Investigational Site

Yvoir, , Belgium

GSK Investigational Site

Calgary, Alberta, Canada

GSK Investigational Site

Vancouver, British Columbia, Canada

GSK Investigational Site

Halifax, Nova Scotia, Canada

GSK Investigational Site

Hamilton, Ontario, Canada

GSK Investigational Site

London, Ontario, Canada

GSK Investigational Site

Oshawa, Ontario, Canada

GSK Investigational Site

Ottawa, Ontario, Canada

GSK Investigational Site

Toronto, Ontario, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Hradec Králové, , Czechia

GSK Investigational Site

Ostrava, , Czechia

GSK Investigational Site

Prague, , Czechia

GSK Investigational Site

Zlín, , Czechia

GSK Investigational Site

Boulogne-Billancourt, , France

GSK Investigational Site

Grenoble, , France

GSK Investigational Site

Montpellier, , France

GSK Investigational Site

Nantes, , France

GSK Investigational Site

Paris, , France

GSK Investigational Site

Pierre-Bénite, , France

GSK Investigational Site

Rennes, , France

GSK Investigational Site

Tours, , France

GSK Investigational Site

Villejuif, , France

GSK Investigational Site

Heidelberg, Baden-Wurttemberg, Germany

GSK Investigational Site

Mannheim, Baden-Wurttemberg, Germany

GSK Investigational Site

Tübingen, Baden-Wurttemberg, Germany

GSK Investigational Site

Munich, Bavaria, Germany

GSK Investigational Site

Würzburg, Bavaria, Germany

GSK Investigational Site

Buxtehude, Lower Saxony, Germany

GSK Investigational Site

Essen, North Rhine-Westphalia, Germany

GSK Investigational Site

Dresden, Saxony, Germany

GSK Investigational Site

Lübeck, Schleswig-Holstein, Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Athens, , Greece

GSK Investigational Site

Athens, , Greece

GSK Investigational Site

Thessaloniki, , Greece

GSK Investigational Site

Milan, Lombardy, Italy

GSK Investigational Site

Milan, Lombardy, Italy

GSK Investigational Site

Milan, Lombardy, Italy

GSK Investigational Site

Pisa, Tuscany, Italy

GSK Investigational Site

Christchurch, , New Zealand

GSK Investigational Site

Dunedin, , New Zealand

GSK Investigational Site

Newtown, Wellington, , New Zealand

GSK Investigational Site

Oslo, , Norway

GSK Investigational Site

Poznan, , Poland

GSK Investigational Site

Warsaw, , Poland

GSK Investigational Site

Warsaw, , Poland

GSK Investigational Site

Chelyabinsk, , Russia

GSK Investigational Site

Magnitogorsk, , Russia

GSK Investigational Site

Moscow, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Gothenburg, , Sweden

GSK Investigational Site

Linköping, , Sweden

GSK Investigational Site

Lund, , Sweden

GSK Investigational Site

Stockholm, , Sweden

GSK Investigational Site

Uppsala, , Sweden

GSK Investigational Site

Zurich, , Switzerland

GSK Investigational Site

Dnipro, , Ukraine

GSK Investigational Site

Kharkiv, , Ukraine

GSK Investigational Site

Kyiv, , Ukraine

GSK Investigational Site

Kyiv, , Ukraine

GSK Investigational Site

Lviv, , Ukraine

GSK Investigational Site

Sumy, , Ukraine

GSK Investigational Site

Sympheropol, , Ukraine

GSK Investigational Site

Ternopil, , Ukraine

GSK Investigational Site

Uzhhorod, , Ukraine

GSK Investigational Site

Cambridge, Cambridgeshire, United Kingdom

GSK Investigational Site

Northwood, Middlesex, United Kingdom

GSK Investigational Site

Sutton, Surrey, United Kingdom

GSK Investigational Site

Aberdeen, , United Kingdom

GSK Investigational Site

Birmingham, , United Kingdom

GSK Investigational Site

Chelmsford, , United Kingdom

GSK Investigational Site

Leeds, , United Kingdom

GSK Investigational Site

London, , United Kingdom

GSK Investigational Site

London, , United Kingdom

GSK Investigational Site

Manchester, , United Kingdom

GSK Investigational Site

Oxford, , United Kingdom

GSK Investigational Site

Southampton, , United Kingdom

Countries

United States; Argentina; Australia; Austria; Belgium; Canada; Czechia; France; Germany; Greece; Italy; New Zealand; Norway; Poland; Russia; Sweden; Switzerland; Ukraine; United Kingdom

References

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.

Reference Type: 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.

Reference Type: RESULT

PMID: 22663011 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30690294 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27172483 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26446943 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24504441 (View on PubMed)

Other Identifiers

114267

Identifier Type: -

Identifier Source: org_study_id