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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase III Randomized, Open-label Study Comparing GSK1120212 to Chemotherapy in Subjects With Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: GSK1120212
* Drug: Chemotherapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK1120212<br>MEK inhibitor | Drug: GSK1120212<br>* MEK inhibitor<br>|
| Active Comparator: Chemotherapy<br>Investigator Choice of DTIC or paclitaxel | Drug: Chemotherapy<br>* Investigator Choice of DTIC or paclitaxel<br>|
| Experimental: Crossover<br>MEK inhibitor after documented progression on Chemotherapy Arm | Drug: GSK1120212<br>* MEK inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival in All Participants | PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed and BRIC-assessed PFS were summarized per RECIST, Version 1.1. 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 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Intend-To-Treat (ITT) Population included all randomized participants regardless of whether or not treatment was administered. | 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 | PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. 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 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. | 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 | PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. 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 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. | 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 | Overall survival was defined as the time from the date of randomization to the date of death due to any cause. | 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 | Overall survival was defined as the time from the date of randomization to the date of death due to any cause. NA indicates data was not available. | Day 1 until death due to any cause (average of 20.3 months) | 
| 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 | OR is defined as the number of participants with evidence of complete response (CR; disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1. | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | 
| Number of Participants With OR as Assessed by the Investigator and Independent Review | OR is defined as the number of participants with evidence of complete response (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1. | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | 
| Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | OR is defined as the number of participants with evidence of complete response (disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1. | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | 
| Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator | OR is defined as the number of participants with evidence of complete response (CR; disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1. | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | 
| Number of Participants With OR Following Cross-over to Trametinib | OR is defined as the number of participants with evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 millimeters in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator in participants following cross-over to Trametinib. The evaluation was carried out by the Investigator per RECIST, Version 1.1. Cross-over Population included the subset of participants who were randomized to CT and who elected to cross-over to Trametinib following disease progression on CT. Only participants who received at least one dose of Trametinib were included in this population. | Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months) | 
| 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 | DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the investigator-assessed (INVA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | 
| 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 | DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the independently-assessed (INDA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | 
| DoR for All Confirmed Responders (CR or PR) as Assessed by the Investigator Review | DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until 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 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INVA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | 
| DoR for All Confirmed Responders (CR or PR) as Assessed by the Independent Review | DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until 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 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INDA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. | Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months) | 
| DoR for All Responders (CR or PR) Following Cross-over to Trametinib as Assessed by the Investigator | DoR is defined as the time from the first documented evidence of CR (disappearance of all extra nodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until 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 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR data were summarized per RECIST, Version 1.1Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. | Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months) | 
| PFS Following Cross-over to Trametinib as Assessed by the Investigator | PFS is defined as the time from the first dose of cross-over therapy to the first documented occurrence of PD or death. PFS was summarized per RECIST, Version 1.1. 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 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. | Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEK inhibitor, Cancer, Metastatic Melanoma, BRAF mutant metastatic melanoma, GSK1120212