Clinical trial NCT01245062: GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma
Official title: A Phase III Randomized, Open-label Study Comparing GSK1120212 to Chemotherapy in Subjects With Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Melanoma
Keywords: MEK inhibitor
Cancer
Metastatic Melanoma
BRAF mutant metastatic melanoma
GSK1120212
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-11-22
Enrollment: 322
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
Secondary outcomes:
measure: Progression-free Survival in All Participants
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: Overall Survival in All Participants
timeFrame: Day 1 until death due to any cause (average of 20.3 months)
measure: Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases
timeFrame: Day 1 until death due to any cause (average of 20.3 months)
measure: Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: Number of Participants With OR as Assessed by the Investigator and Independent Review
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: Number of Participants With OR Following Cross-over to Trametinib
timeFrame: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)
measure: Duration of Response (DoR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Investigator Review
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: DoR for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Independent Review
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: DoR for All Confirmed Responders (CR or PR) as Assessed by the Investigator Review
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: DoR for All Confirmed Responders (CR or PR) as Assessed by the Independent Review
timeFrame: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)
measure: DoR for All Responders (CR or PR) Following Cross-over to Trametinib as Assessed by the Investigator
timeFrame: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)
measure: PFS Following Cross-over to Trametinib as Assessed by the Investigator
timeFrame: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: Fort Myers
country: United States
facility: GSK Investigational Site
state: Florida
city: Athens
country: United States
facility: GSK Investigational Site
state: Georgia
city: Marietta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Iowa City
country: United States
facility: GSK Investigational Site
state: Iowa
city: Metairie
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Morristown
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Columbia
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Chattanooga
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Garran
country: Australia
facility: GSK Investigational Site
state: Australian Capital Territory
city: Port Macquarie
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Waratah
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: South Brisbane
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Townsville
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Woolloongabba
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Kurralta Park
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Woodville
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Heidelberg
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Graz
country: Austria
facility: GSK Investigational Site
city: Wien
country: Austria
facility: GSK Investigational Site
city: Brussels
country: Belgium
facility: GSK Investigational Site
city: Charleroi
country: Belgium
facility: GSK Investigational Site
city: Gent
country: Belgium
facility: GSK Investigational Site
city: Jette
country: Belgium
facility: GSK Investigational Site
city: Kortrijk
country: Belgium
facility: GSK Investigational Site
city: Leuven
country: Belgium
facility: GSK Investigational Site
city: Wilrijk
country: Belgium
facility: GSK Investigational Site
city: Yvoir
country: Belgium
facility: GSK Investigational Site
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Halifax
country: Canada
facility: GSK Investigational Site
state: Nova Scotia
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Oshawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Hradec Kralove
country: Czechia
facility: GSK Investigational Site
city: Ostrava
country: Czechia
facility: GSK Investigational Site
city: Praha 2
country: Czechia
facility: GSK Investigational Site
city: Zlin
country: Czechia
facility: GSK Investigational Site
city: Boulogne-Billancourt
country: France
facility: GSK Investigational Site
city: Grenoble
country: France
facility: GSK Investigational Site
city: Montpellier
country: France
facility: GSK Investigational Site
city: Nantes
country: France
facility: GSK Investigational Site
city: Paris Cedex 10
country: France
facility: GSK Investigational Site
city: Pierre-Benite cedex
country: France
facility: GSK Investigational Site
city: Rennes
country: France
facility: GSK Investigational Site
city: Tours
country: France
facility: GSK Investigational Site
city: Villejuif
country: France
facility: GSK Investigational Site
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Mannheim
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Tuebingen
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Wuerzburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Buxtehude
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Luebeck
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Pisa
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Christchurch
country: New Zealand
facility: GSK Investigational Site
city: Dunedin
country: New Zealand
facility: GSK Investigational Site
city: Newtown, Wellington
country: New Zealand
facility: GSK Investigational Site
city: Oslo
country: Norway
facility: GSK Investigational Site
city: Poznan
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Chelyabinsk
country: Russian Federation
facility: GSK Investigational Site
city: Magnitogorsk
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Goteborg
country: Sweden
facility: GSK Investigational Site
city: Linkoping
country: Sweden
facility: GSK Investigational Site
city: Lund
country: Sweden
facility: GSK Investigational Site
city: Stockholm
country: Sweden
facility: GSK Investigational Site
city: Uppsala
country: Sweden
facility: GSK Investigational Site
city: Zurich
country: Switzerland
facility: GSK Investigational Site
city: Dnepropetrovsk
country: Ukraine
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Lviv
country: Ukraine
facility: GSK Investigational Site
city: Sumy
country: Ukraine
facility: GSK Investigational Site
city: Sympheropol
country: Ukraine
facility: GSK Investigational Site
city: Ternopil
country: Ukraine
facility: GSK Investigational Site
city: Uzhgorod
country: Ukraine
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
state: Cambridgeshire
city: Northwood
country: United Kingdom
facility: GSK Investigational Site
state: Middlesex
city: Sutton
country: United Kingdom
facility: GSK Investigational Site
state: Surrey
city: Aberdeen
country: United Kingdom
facility: GSK Investigational Site
city: Birmingham
country: United Kingdom
facility: GSK Investigational Site
city: Chelmsford
country: United Kingdom
facility: GSK Investigational Site
city: Leeds
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
city: Oxford
country: United Kingdom
facility: GSK Investigational Site
city: Southampton
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.