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

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

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.

Study Overview

• Status: Completed
• Conditions: Melanoma and Brain Metastases
• Intervention / Treatment: Drug: Dabrafenib; Drug: Trametinib

• Study Type: Interventional
• Enrollment (Actual): 127
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • North Sydney, New South Wales, Australia, 2060
      • Novartis Investigative Site
  • Queensland
    • Greenslopes, Queensland, Australia, 4120
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Novartis Investigative Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Novartis Investigative Site
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H2W 1S6
      • Novartis Investigative Site
• France
  • 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
    • Novartis Investigative Site
• Germany
  • Baden-Wuerttemberg
    • Heidelberg, Baden-Wuerttemberg, Germany, 69120
      • Novartis Investigative Site
    • Tuebingen, Baden-Wuerttemberg, Germany, 72076
      • Novartis Investigative Site
  • Bayern
    • Muenchen, Bayern, Germany, 80337
      • Novartis Investigative Site
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30449
      • Novartis Investigative Site
  • Nordrhein-Westfalen
    • Koeln, Nordrhein-Westfalen, Germany, 50937
      • Novartis Investigative Site
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • Novartis Investigative Site
  • Thueringen
    • Gera, Thueringen, Germany, 07548
      • Novartis Investigative Site
• Italy
  • Lombardia
    • Milano, Lombardia, Italy, 20133
      • Novartis Investigative Site
    • Milano, Lombardia, Italy, 20141
      • Novartis Investigative Site
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Novartis Investigative Site
• Spain
  • 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
    • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35243
      • Novartis Investigative Site
  • California
    • San Francisco, California, United States, 94115
      • Novartis Investigative Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Novartis Investigative Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Novartis Investigative Site
    • Atlanta, Georgia, United States, 30341
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Novartis Investigative Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Novartis Investigative Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Novartis Investigative Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Novartis Investigative Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Novartis Investigative Site
  • Texas
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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, Marquez-Rodas I, Del Vecchio M, Lebbe C, Meyer N, Zhang Y, Huang Y, Mookerjee B, Long GV. Dabrafenib plus trametinib in patients with BRAFV600-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.

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2014
• Primary Completion (Actual): May 12, 2017
• Study Completion (Actual): February 14, 2018

Study Registration Dates

• First Submitted: December 19, 2013
• First Submitted That Met QC Criteria: January 16, 2014
• First Posted (Estimate): January 20, 2014

Study Record Updates

• Last Update Posted (Actual): May 21, 2019
• Last Update Submitted That Met QC Criteria: May 20, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Intracranial; Metastatic Melanoma; BRAF V600E mutation; BRAF V600K mutation; BRAF V600R mutation; BRAF V600D mutation; Brain metastases BRAF inhibitor
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Neoplasm Metastasis; Brain Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib; Dabrafenib
• Other Study ID Numbers: 117277

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No