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

Primary Purpose

Melanoma and Brain Metastases

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Dabrafenib

Trametinib

About this trial

This is an interventional treatment trial for Melanoma and Brain Metastases focused on measuring BRAF V600K mutation, Metastatic Melanoma, BRAF V600R mutation, BRAF V600D mutation, BRAF V600E mutation, Brain metastases BRAF inhibitor, Intracranial

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Cohort A

Cohort B

Cohort C

Cohort D

Arm Description

Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.

Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

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

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

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.

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

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

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

Full Information

NCT ID

NCT02039947

First Posted

December 19, 2013

Last Updated

May 20, 2019

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT02039947

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2019

Overall Recruitment Status

Completed

Study Start Date

February 21, 2014 (Actual)

Primary Completion Date

May 12, 2017 (Actual)

Study Completion Date

February 14, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma and Brain Metastases

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

127 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort A

Arm Type

Experimental

Arm Description

Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.

Arm Title

Cohort B

Arm Type

Experimental

Arm Description

Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

Arm Title

Cohort C

Arm Type

Experimental

Arm Description

Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

Arm Title

Cohort D

Arm Type

Experimental

Arm Description

Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

Intervention Type

Drug

Intervention Name(s)

Dabrafenib

Intervention Description

Dabrafenib will be provided as 50 mg and 75 mg capsules

Intervention Type

Drug

Intervention Name(s)

Trametinib

Intervention Description

Trametinib will be provided as 0.5 mg and 2.0 mg tablets

Primary Outcome Measure Information:

Title

Intracranial Response (IR) Rate in Cohort A

Description

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.

Time Frame

From the start of treatment until disease progression or the start of new anti-cancer therapy

Secondary Outcome Measure Information:

Title

Intracranial Response Rate of Cohorts B, C and D

Description

Time Frame

Approximately 2 years

Title

Disease Control for Intracranial, Extracranial and Overall Response for Each Cohort

Description

Time Frame

Approximately 2 years

Title

Extracranial Response Rate (ER) for Each Cohort

Description

Time Frame

Approximately 2 years

Title

Overall Response (OR) for Each Cohort

Description

Time Frame

Approximately 2 years

Title

Duration of Intracranial, Extracranial and Overall Response for Each Cohort

Description

Time Frame

From first documented evidence of CR or PR until time of first documented intracranial, extracranial, or overall disease progression

Title

Progression-free Survival (PFS) for Each Cohort Based on Investigator Assessment

Description

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

Time Frame

From the first dose to the earliest date of disease progression or death

Title

Overall Survival (OS) for Each Cohort

Description

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

Time Frame

From the first dose to death

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

Birmingham

State/Province

Alabama

ZIP/Postal Code

35243

Country

United States

Facility Name

Novartis Investigative Site

City

San Francisco

State/Province

California

ZIP/Postal Code

94115

Country

United States

Facility Name

Novartis Investigative Site

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

Novartis Investigative Site

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Novartis Investigative Site

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30341

Country

United States

Facility Name

Novartis Investigative Site

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

Novartis Investigative Site

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599

Country

United States

Facility Name

Novartis Investigative Site

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

Facility Name

Novartis Investigative Site

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15232

Country

United States

Facility Name

Novartis Investigative Site

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

Facility Name

Novartis Investigative Site

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Novartis Investigative Site

City

North Sydney

State/Province

New South Wales

ZIP/Postal Code

2060

Country

Australia

Facility Name

Novartis Investigative Site

City

Greenslopes

State/Province

Queensland

ZIP/Postal Code

4120

Country

Australia

Facility Name

Novartis Investigative Site

City

Melbourne

State/Province

Victoria

ZIP/Postal Code

3004

Country

Australia

Facility Name

Novartis Investigative Site

City

Edmonton

State/Province

Alberta

ZIP/Postal Code

T6G 1Z2

Country

Canada

Facility Name

Novartis Investigative Site

City

Hamilton

State/Province

Ontario

ZIP/Postal Code

L8V 5C2

Country

Canada

Facility Name

Novartis Investigative Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2M9

Country

Canada

Facility Name

Novartis Investigative Site

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H2W 1S6

Country

Canada

Facility Name

Novartis Investigative Site

City

Boulogne-Billancourt

ZIP/Postal Code

92100

Country

France

Facility Name

Novartis Investigative Site

City

Lille

ZIP/Postal Code

59037

Country

France

Facility Name

Novartis Investigative Site

City

Marseille Cedex 5

ZIP/Postal Code

13385

Country

France

Facility Name

Novartis Investigative Site

City

Montpellier cedex 5

ZIP/Postal Code

34295

Country

France

Facility Name

Novartis Investigative Site

City

Nantes Cedex 1

ZIP/Postal Code

44093

Country

France

Facility Name

Novartis Investigative Site

City

Paris Cedex 10

ZIP/Postal Code

75475

Country

France

Facility Name

Novartis Investigative Site

City

Pierre-Benite cedex

ZIP/Postal Code

69495

Country

France

Facility Name

Novartis Investigative Site

City

Poitiers

ZIP/Postal Code

86021

Country

France

Facility Name

Novartis Investigative Site

City

Rennes Cedex

ZIP/Postal Code

35042

Country

France

Facility Name

Novartis Investigative Site

City

Toulouse cedex

ZIP/Postal Code

31052

Country

France

Facility Name

Novartis Investigative Site

City

Villejuif cedex

ZIP/Postal Code

94805

Country

France

Facility Name

Novartis Investigative Site

City

Heidelberg

State/Province

Baden-Wuerttemberg

ZIP/Postal Code

69120

Country

Germany

Facility Name

Novartis Investigative Site

City

Tuebingen

State/Province

Baden-Wuerttemberg

ZIP/Postal Code

72076

Country

Germany

Facility Name

Novartis Investigative Site

City

Muenchen

State/Province

Bayern

ZIP/Postal Code

80337

Country

Germany

Facility Name

Novartis Investigative Site

City

Hannover

State/Province

Niedersachsen

ZIP/Postal Code

30449

Country

Germany

Facility Name

Novartis Investigative Site

City

Koeln

State/Province

Nordrhein-Westfalen

ZIP/Postal Code

50937

Country

Germany

Facility Name

Novartis Investigative Site

City

Kiel

State/Province

Schleswig-Holstein

ZIP/Postal Code

24105

Country

Germany

Facility Name

Novartis Investigative Site

City

Gera

State/Province

Thueringen

ZIP/Postal Code

07548

Country

Germany

Facility Name

Novartis Investigative Site

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20133

Country

Italy

Facility Name

Novartis Investigative Site

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20141

Country

Italy

Facility Name

Novartis Investigative Site

City

Padova

State/Province

Veneto

ZIP/Postal Code

35128

Country

Italy

Facility Name

Novartis Investigative Site

City

Barcelona

ZIP/Postal Code

08036

Country

Spain

Facility Name

Novartis Investigative Site

City

Las Palmas De Gran Canaria

ZIP/Postal Code

35016

Country

Spain

Facility Name

Novartis Investigative Site

City

Madrid

ZIP/Postal Code

28007

Country

Spain

Facility Name

Novartis Investigative Site

City

Malaga

ZIP/Postal Code

29010

Country

Spain

Facility Name

Novartis Investigative Site

City

Palma de Mallorca

ZIP/Postal Code

07198

Country

Spain

Facility Name

Novartis Investigative Site

City

Pamplona

ZIP/Postal Code

31008

Country

Spain

Facility Name

Novartis Investigative Site

City

Valencia

ZIP/Postal Code

46009

Country

Spain

Facility Name

Novartis Investigative Site

City

Zaragoza

ZIP/Postal Code

50009

Country

Spain

12. IPD Sharing Statement

Citations:

PubMed Identifier

33587894

Citation

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.

Results Reference

derived

PubMed Identifier

28592387

Citation

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.

Results Reference

derived

Learn more about this trial

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

Melanoma and Brain Metastases

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial