Study to Evaluate Treatment of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain

Study Overview
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Brief Summary
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This is a multi-cohort, open label, Phase II study with Dabrafenib (GSK2118436) and Trametinib (GSK1120212) combination therapy in subject with BRAF mutation-positive melanoma that has metastasized to the brain. This study will evaluate the safety and efficacy of 4 cohorts. Cohorts will consist of; V600 E, D, K, R mutations, metastases to the brain, symptomatic and asymptomatic, with or without prior local (brain) therapy, with or without prior local (brain) therapy, and range of ECOG scores from 0-2.

Official Title
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BRF117277: A Phase II, Open-Label, Multicentre Study of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain

Conditions
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Melanoma and Brain Metastases

Intervention / Treatment
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* Drug: Dabrafenib
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ECOG Performance Status range of 0-2 Histologically confirmed cutaneous metastatic melanoma of V600 E, K, D or R. May be systemic naïve or received up to two previous systemic treatment regimens for metastatic melanoma. Must be able to undergo MRI and have at least one measurable intracranial lesion for which specific criteria have to be met. Exclusion Criteria: Prior treatment with any BRAF inhibitor or any mitogen-activated protein/extracellular signal-regulated kinase inhibitor. Anti-cancer therapy or investigational anti-cancer therapy or chemotherapy without delayed toxicity within treatment specific timeframe. Treatment with stereotactic radiosurgery or treatment with whole-brain radiation within treatment specific timeframe. Any presence of leptomeningeal disease or any parenchymal brain metastasis History of another malignancy, some exceptions may apply. A history or evidence of cardiovascular risk- specific criteria have to be met A history or current evidence/risk of retinal vein occlusion or retinal pigment epithelial detachment - specific criteria have to be met.

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: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity. | Drug: Dabrafenib<br>* Dabrafenib will be provided as 50 mg and 75 mg capsules<br>Drug: Trametinib<br>* Trametinib will be provided as 0.5 mg and 2.0 mg tablets<br>|
| Experimental: Cohort B<br>Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity | Drug: Dabrafenib<br>* Dabrafenib will be provided as 50 mg and 75 mg capsules<br>Drug: Trametinib<br>* Trametinib will be provided as 0.5 mg and 2.0 mg tablets<br>|
| Experimental: Cohort C<br>Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity | Drug: Dabrafenib<br>* Dabrafenib will be provided as 50 mg and 75 mg capsules<br>Drug: Trametinib<br>* Trametinib will be provided as 0.5 mg and 2.0 mg tablets<br>|
| Experimental: Cohort D<br>Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity | Drug: Dabrafenib<br>* Dabrafenib will be provided as 50 mg and 75 mg capsules<br>Drug: Trametinib<br>* Trametinib will be provided as 0.5 mg and 2.0 mg tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial Response (IR) Rate in Cohort A | The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response. | From the start of treatment until disease progression or the start of new anti-cancer therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial Response Rate of Cohorts B, C and D | The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response. No hypothesis testing completed for cohort A, B,C and D | Approximately 2 years | 
| Disease Control for Intracranial, Extracranial and Overall Response for Each Cohort | Disease Control rate is defined as the percentage of subjects achieving a confirmed intracranial/extracranial/overall CR or PR or SD or Non-CR/Non-PD. This is based on investigator-assessed response. No hypothesis testing completed for cohort A, B,C and D | Approximately 2 years | 
| Extracranial Response Rate (ER) for Each Cohort | Extracranial Response Rate was defined as the percentage of participants with Complete response (CR) or Partial response (PR) at anytime. This is based on investigator-assessed response. No hypothesis testing completed for cohort A,B,C and D | Approximately 2 years | 
| Overall Response (OR) for Each Cohort | the number of subjects with a confirmed overall Complete response (CR) or Partial response (PR) by investigator assessment using the Response evaluation criteria in solid tumors (RECIST 1.1 criteria). To determine the overall response, all target and non-target lesions will be assessed using modified RECIST 1.1 criteria. | Approximately 2 years | 
| Duration of Intracranial, Extracranial and Overall Response for Each Cohort | Duration of intracranial, extracranial and overall response, are defined as the time from first documented evidence of CR or PR until time of first documented intracranial, extracranial, or overall disease progression. No hypothesis testing completed for cohort A,B,C and D | From first documented evidence of CR or PR until time of first documented intracranial, extracranial, or overall disease progression | 
| Progression-free Survival (PFS) for Each Cohort Based on Investigator Assessment | PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. No hypothesis testing completed for cohort A,B,C and D | From the first dose to the earliest date of disease progression or death | 
| Overall Survival (OS) for Each Cohort | Overall survival (OS) is defined as the time from the first dose until death due to any cause. No hypothesis testing completed for cohort A,B,C and D | From the first dose to death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRAF V600D mutation, BRAF V600K mutation, Metastatic Melanoma, BRAF V600R mutation, BRAF V600E mutation, Brain metastases BRAF inhibitor, Intracranial