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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02039947

Enrollment

127

Registered

2014-01-20

Start date

2014-02-21

Completion date

2018-02-14

Last updated

2019-05-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Melanoma and Brain Metastases

Keywords

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

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.

Interventions

DRUGDabrafenib

Dabrafenib will be provided as 50 mg and 75 mg capsules

DRUGTrametinib

Trametinib will be provided as 0.5 mg and 2.0 mg tablets

Study design

Allocation

NON_RANDOMIZED

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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.

Design outcomes

Primary

Measure	Time frame	Description
Intracranial Response (IR) Rate in Cohort A	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

Measure	Time frame	Description
Disease Control for Intracranial, Extracranial and Overall Response for Each Cohort	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	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	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.
Intracranial Response Rate of Cohorts B, C and D	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
Progression-free Survival (PFS) for Each Cohort Based on Investigator Assessment	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	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
Duration of Intracranial, Extracranial and Overall Response for Each Cohort	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

Countries

Australia, Canada, France, Germany, Italy, Spain, United States

Participant flow

Pre-assignment details

A subject was considered to have completed the study if the subject died during the study treatment or follow-up period or (for subject in Cohort A) had at least 3 years follow-up from the date of first dose of study treatment at the end of the study. All subjects achieved that definition and then the study ended.

Participants by arm

Arm	Count
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.	76
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	16
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	16
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	17
Total	125

Baseline characteristics

Characteristic	Cohort A	Total	Cohort D	Cohort C	Cohort B
Age, Continuous	53.2 Years STANDARD_DEVIATION 14.69	54.2 Years STANDARD_DEVIATION 14.29	47.5 Years STANDARD_DEVIATION 13.01	65.6 Years STANDARD_DEVIATION 10.4	55.1 Years STANDARD_DEVIATION 11.05
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	76 Participants	125 Participants	17 Participants	16 Participants	16 Participants
Sex: Female, Male Female	36 Participants	53 Participants	6 Participants	5 Participants	6 Participants
Sex: Female, Male Male	40 Participants	72 Participants	11 Participants	11 Participants	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	54 / 76	10 / 16	15 / 16	13 / 17	92 / 125
other Total, other adverse events	74 / 76	16 / 16	16 / 16	17 / 17	123 / 125
serious Total, serious adverse events	26 / 76	5 / 16	4 / 16	9 / 17	44 / 125

Outcome results

Primary

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.

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

Population: All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population.

Arm	Measure	Value (NUMBER)
Cohort A	Intracranial Response (IR) Rate in Cohort A	45 Number of participants

p-value: <0.000195% CI: [47.3, 70.4]percent

Secondary

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

Time frame: Approximately 2 years