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

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ClinicalTrials.gov Identifier: NCT02039947

Recruitment Status : Completed

First Posted : January 20, 2014

Results First Posted : May 21, 2019

Last Update Posted : May 21, 2019

Sponsor:

Information provided by (Responsible Party):

Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Melanoma and Brain Metastases	Drug: Dabrafenib Drug: Trametinib	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	127 participants
Allocation:	Non-Randomized
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	February 21, 2014
Actual Primary Completion Date :	May 12, 2017
Actual Study Completion Date :	February 14, 2018

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma

MedlinePlus related topics: Melanoma

Drug Information available for: Trametinib Dabrafenib

Genetic and Rare Diseases Information Center resources: Neuroendocrine Tumor Neuroepithelioma

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort A 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 Dabrafenib will be provided as 50 mg and 75 mg capsules Drug: Trametinib Trametinib will be provided as 0.5 mg and 2.0 mg tablets
Experimental: Cohort B 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 Dabrafenib will be provided as 50 mg and 75 mg capsules Drug: Trametinib Trametinib will be provided as 0.5 mg and 2.0 mg tablets
Experimental: Cohort C 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 Dabrafenib will be provided as 50 mg and 75 mg capsules Drug: Trametinib Trametinib will be provided as 0.5 mg and 2.0 mg tablets
Experimental: Cohort D 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 Dabrafenib will be provided as 50 mg and 75 mg capsules Drug: Trametinib Trametinib will be provided as 0.5 mg and 2.0 mg tablets

Outcome Measures

Primary Outcome Measures :

Intracranial Response (IR) Rate in Cohort A [ Time Frame: From the start of treatment until disease progression or the start of new anti-cancer therapy ]
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.

Secondary Outcome Measures :

Intracranial Response Rate of Cohorts B, C and D [ Time Frame: Approximately 2 years ]
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
Disease Control for Intracranial, Extracranial and Overall Response for Each Cohort [ Time Frame: Approximately 2 years ]
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
Extracranial Response Rate (ER) for Each Cohort [ Time Frame: Approximately 2 years ]
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
Overall Response (OR) for Each Cohort [ Time Frame: Approximately 2 years ]
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.
Duration of Intracranial, Extracranial and Overall Response for Each Cohort [ Time Frame: From first documented evidence of CR or PR until time of first documented intracranial, extracranial, or overall disease progression ]
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
Progression-free Survival (PFS) for Each Cohort Based on Investigator Assessment [ Time Frame: From the first dose to the earliest date of disease progression or death ]
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
Overall Survival (OS) for Each Cohort [ Time Frame: From the first dose to death ]
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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02039947

Locations

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United States, Alabama
Novartis Investigative Site
Birmingham, Alabama, United States, 35243
United States, California
Novartis Investigative Site
San Francisco, California, United States, 94115
United States, Colorado
Novartis Investigative Site
Aurora, Colorado, United States, 80045
United States, Georgia
Novartis Investigative Site
Atlanta, Georgia, United States, 30322
Novartis Investigative Site
Atlanta, Georgia, United States, 30341
United States, Massachusetts
Novartis Investigative Site
Boston, Massachusetts, United States, 02215
United States, North Carolina
Novartis Investigative Site
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Novartis Investigative Site
Columbus, Ohio, United States, 43210
United States, Pennsylvania
Novartis Investigative Site
Pittsburgh, Pennsylvania, United States, 15232
United States, Tennessee
Novartis Investigative Site
Nashville, Tennessee, United States, 37232
United States, Texas
Novartis Investigative Site
Houston, Texas, United States, 77030
Australia, New South Wales
Novartis Investigative Site
North Sydney, New South Wales, Australia, 2060
Australia, Queensland
Novartis Investigative Site
Greenslopes, Queensland, Australia, 4120
Australia, Victoria
Novartis Investigative Site
Melbourne, Victoria, Australia, 3004
Canada, Alberta
Novartis Investigative Site
Edmonton, Alberta, Canada, T6G 1Z2
Canada, Ontario
Novartis Investigative Site
Hamilton, Ontario, Canada, L8V 5C2
Novartis Investigative Site
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Novartis Investigative Site
Montreal, Quebec, Canada, H2W 1S6
France
Novartis Investigative Site
Boulogne-Billancourt, France, 92100
Novartis Investigative Site
Lille, France, 59037
Novartis Investigative Site
Marseille Cedex 5, France, 13385
Novartis Investigative Site
Montpellier cedex 5, France, 34295
Novartis Investigative Site
Nantes Cedex 1, France, 44093
Novartis Investigative Site
Paris Cedex 10, France, 75475
Novartis Investigative Site
Pierre-Benite cedex, France, 69495
Novartis Investigative Site
Poitiers, France, 86021
Novartis Investigative Site
Rennes Cedex, France, 35042
Novartis Investigative Site
Toulouse cedex, France, 31052
Novartis Investigative Site
Villejuif cedex, France, 94805
Germany
Novartis Investigative Site
Heidelberg, Baden-Wuerttemberg, Germany, 69120
Novartis Investigative Site
Tuebingen, Baden-Wuerttemberg, Germany, 72076
Novartis Investigative Site
Muenchen, Bayern, Germany, 80337
Novartis Investigative Site
Hannover, Niedersachsen, Germany, 30449
Novartis Investigative Site
Koeln, Nordrhein-Westfalen, Germany, 50937
Novartis Investigative Site
Kiel, Schleswig-Holstein, Germany, 24105
Novartis Investigative Site
Gera, Thueringen, Germany, 07548
Italy
Novartis Investigative Site
Milano, Lombardia, Italy, 20133
Novartis Investigative Site
Milano, Lombardia, Italy, 20141
Novartis Investigative Site
Padova, Veneto, Italy, 35128
Spain
Novartis Investigative Site
Barcelona, Spain, 08036
Novartis Investigative Site
Las Palmas De Gran Canaria, Spain, 35016
Novartis Investigative Site
Madrid, Spain, 28007
Novartis Investigative Site
Malaga, Spain, 29010
Novartis Investigative Site
Palma de Mallorca, Spain, 07198
Novartis Investigative Site
Pamplona, Spain, 31008
Novartis Investigative Site
Valencia, Spain, 46009
Novartis Investigative Site
Zaragoza, Spain, 50009

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

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Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Statistical Analysis Plan [PDF] March 5, 2018

Study Protocol [PDF] June 21, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Syeda MM, Wiggins JM, Corless BC, Long GV, Flaherty KT, Schadendorf D, Nathan PD, Robert C, Ribas A, Davies MA, Grob JJ, Gasal E, Squires M, Marker M, Garrett J, Brase JC, Polsky D. Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study. Lancet Oncol. 2021 Mar;22(3):370-380. doi: 10.1016/S1470-2045(20)30726-9. Epub 2021 Feb 12.

Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, Chiarion-Sileni V, Thomas L, Lesimple T, Mortier L, Moschos SJ, Hogg D, Márquez-Rodas I, Del Vecchio M, Lebbé C, Meyer N, Zhang Y, Huang Y, Mookerjee B, Long GV. Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017 Jul;18(7):863-873. doi: 10.1016/S1470-2045(17)30429-1. Epub 2017 Jun 4.

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Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT02039947
Other Study ID Numbers:	117277
First Posted:	January 20, 2014 Key Record Dates
Results First Posted:	May 21, 2019
Last Update Posted:	May 21, 2019
Last Verified:	May 2019

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):


BRAF V600K mutation Metastatic Melanoma BRAF V600R mutation BRAF V600D mutation	BRAF V600E mutation Brain metastases BRAF inhibitor Intracranial

Additional relevant MeSH terms:

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Melanoma Neoplasm Metastasis Brain Neoplasms Neuroendocrine Tumors Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Nerve Tissue Nevi and Melanomas Neoplastic Processes Pathologic Processes	Central Nervous System Neoplasms Nervous System Neoplasms Neoplasms by Site Brain Diseases Central Nervous System Diseases Nervous System Diseases Trametinib Dabrafenib Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action

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