Clinical Trial Results:
A Phase II (BRF113710) single-arm, open-label study of dabrafenib (GSK2118436) in previously treated BRAF mutant metastatic melanoma
Summary
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EudraCT number |
2009-015297-36 |
Trial protocol |
FR DE IT |
Global end of trial date |
17 Jun 2016
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Results information
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Results version number |
v2(current) |
This version publication date |
21 Oct 2017
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First version publication date |
02 Jul 2017
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Other versions |
v1 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
113710
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
GlaxoSmithKline
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Sponsor organisation address |
980 Great West Road, Brentford, Middlesex, United Kingdom,
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Public contact |
GSK Response Center, GlaxoSmithKline, 866 435-7343,
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Scientific contact |
GSK Response Center, GlaxoSmithKline, 866 435-7343,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Oct 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
17 Jun 2016
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of the study is to assess the overall response rate (ORR), defined as the proportion of participants with investigator-assessed complete responses or partial responses, in participants with metastatic melanoma treated with the oral agent GSK2118436 in subjects.
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Protection of trial subjects |
Not Applicable
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Aug 2010
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 8
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Country: Number of subjects enrolled |
France: 21
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Country: Number of subjects enrolled |
Germany: 20
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Country: Number of subjects enrolled |
Italy: 14
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Country: Number of subjects enrolled |
United States: 29
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Worldwide total number of subjects |
92
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EEA total number of subjects |
55
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
65
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From 65 to 84 years |
27
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85 years and over |
0
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Recruitment
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Recruitment details |
Eligible participants received Dabrafenib (GSK2118436) 150 milligram (mg) twice daily and continued on treatment until disease progression, death, unacceptable adverse event (AE), or early termination of the study. The total duration of the study including a long-term follow-up phase was 5 years. | ||||||||||||||||
Pre-assignment
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Screening details |
A total of 211 participants with histologically confirmed BRAF mutation positive metastatic melanoma (Stage IV) were screened for eligibility. 152 participants had a BRAF V600E or V600K mutation and 92 participants with positive mutation were included in the study. | ||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||
Arms
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Arm title
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GSK2118436 150 mg | ||||||||||||||||
Arm description |
Participants received GSK2118436 (gelatin capsules) 150 mg orally twice a day and continued on treatment until disease progression, death, or unacceptable AEs . Participants who are benefiting from GSK2118436 at the time of study completion will have the option to enter Study BRF114144 (NCT01231594), which is a rollover study for GSK2118436. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Dabrafenib (GSK2118436)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Debrafenib 150 milligram (mg) was administered twice daily under fasting conditions, either 1 hour before or 2 hours after a meal with approximately 200 milliliter (mL) of water.
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Baseline characteristics reporting groups
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Reporting group title |
GSK2118436 150 mg
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Reporting group description |
Participants received GSK2118436 (gelatin capsules) 150 mg orally twice a day and continued on treatment until disease progression, death, or unacceptable AEs . Participants who are benefiting from GSK2118436 at the time of study completion will have the option to enter Study BRF114144 (NCT01231594), which is a rollover study for GSK2118436. | |||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
GSK2118436 150 mg
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Reporting group description |
Participants received GSK2118436 (gelatin capsules) 150 mg orally twice a day and continued on treatment until disease progression, death, or unacceptable AEs . Participants who are benefiting from GSK2118436 at the time of study completion will have the option to enter Study BRF114144 (NCT01231594), which is a rollover study for GSK2118436. |
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End point title |
Number of participants with a best overall response of confirmed complete response (CR) or partial response (PR) as assessed by the investigator for participants who had a BRAF V600E mutation [1] | ||||||||||
End point description |
A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 millimeter (mm) in the short axis.) or PR (at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). To be assigned a status of PR or CR, a confirmatory disease assessment was required at Week 12 if an initial response was seen at the Week 6 scan. Initial responses (CR/PR) that occured at Week 12 or later were required to be confirmed not less than 4 weeks and not more than 6 weeks after the criteria for response were first met. The analysis was performed on Primary efficacy Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600E mutation. The estimated value for the percentage of participants was 59 with 95% CI as 48.2-70.3.
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End point type |
Primary
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End point timeframe |
Up to 60 months
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The estimated value for the percentage of participants and 95% CI was presented in End Point Details Description as it is a single arm study. |
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Notes [2] - Primary efficacy Population |
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No statistical analyses for this end point |
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End point title |
Number of participants with a best overall response of CR or PR as assessed by the investigator and an independent reviewer for participants who had a BRAF V600K mutation | ||||||||||
End point description |
A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). To be assigned a status of PR or CR, a confirmatory disease assessment had to have been performed at Week 12 if an initial response was seen at the Week 6 scan. Initial responses (CR/PR) that occured at Week 12 or later should have been confirmed not less than 4 weeks and not more than 6 weeks after the criteria for response were first met. The analysis was performed on Secondary efficacy analysis Population which comprised of all participants who received at least one dose of GSK2118436 (All Treated Participants Population) and had a BRAF V600K mutation.
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [3] - Secondary Efficacy Population |
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No statistical analyses for this end point |
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End point title |
Progression-free Survival (PFS) as assessed by the investigator and an independent reviewer for participants who had a BRAF V600E mutation | ||||||||||
End point description |
PFS is defined as the interval between the first dose of study medication and the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or progression minus date of first dose plus 1 day. Kaplan-Meier model was used to estimate the median and 95 percent confidence interval (CI). For participants who received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS was censored at the last adequate assessment. For participants who did not have a documented date of progression or death, PFS was censored at the date of last adequate assessment.
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [4] - Primary Efficacy Population |
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No statistical analyses for this end point |
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End point title |
Progression-free Survival (PFS) as assessed by the investigator and an independent reviewer for participants who had a BRAF V600K mutation | ||||||||||
End point description |
PFS is defined as the interval between the first dose of study medication and the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or progression minus date of first dose plus 1 day. Kaplan-Meier model was used to estimate the median and 95 percent CI. For participants who received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS was censored at the last adequate assessment. For participants who did not have a documented date of progression or death, PFS was censored at the date of last adequate assessment.
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [5] - Secondary Efficacy Population |
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No statistical analyses for this end point |
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End point title |
Duration of response as assessed by the investigator and an independent reviewer for participants who had a BRAF V600E mutation | ||||||||||
End point description |
Duration of response for participants with either a CR or PR is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression or death due to any cause. Duration of response was estimated using Kaplan-Meier model and the median and 95 percent CI was presented. The analysis was performed on Primary efficacy Population and only those participants who had a CR or PR were analyzed.
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [6] - Primary Efficacy Population |
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No statistical analyses for this end point |
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End point title |
Duration of response as assessed by the investigator and an independent reviewer for participants who had a BRAF V600K mutation | ||||||||||
End point description |
Duration of response for participants with either a CR or PR is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression or death due to any cause. Duration of response was estimated using Kaplan-Meier model and the median and 95 percent CI was presented. The analysis was performed on Secondary efficacy Population and only those participants who had a CR or PR were analyzed.
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [7] - Secondary Efficacy Population |
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No statistical analyses for this end point |
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End point title |
Overall survival for participants who had a BRAF V600E mutation | ||||||||||
End point description |
Overall survival is defined as the time from the first dose of study medication until death due to any cause. For participants who did not die, overall survival was censored at the date of last contact. Overall survival was estimated using kaplan-Meier model and median and 95 percent CI was presented. The estimated value for the percentage of participants was 20 with 95% CI as 11.6-29.8.
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [8] - Primary Efficacy Population |
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No statistical analyses for this end point |
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End point title |
Overall survival for participants who had a BRAF V600K mutation | ||||||||||
End point description |
Overall survival is defined as the time from the first dose of study medication until death due to any cause. For participants who did not die, overall survival was censored at the date of last contact. Overall survival was estimated using Kaplan-Meier model and median and 95 percent CI was presented. The estimated value for the percentage of participants was 13 with 95% CI as 2.2-34.6.
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End point type |
Secondary
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End point timeframe |
From the first dose to death due to any cause (up to 60 months)
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Notes [9] - Secondary Efficacy Population |
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No statistical analyses for this end point |
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End point title |
Number of participants with AEs and Serious Adverse Events (SAEs) | ||||||||||
End point description |
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs including systemic allergic and non-allergic reactions as well as local site injection-related reactions were counted throughout treatment phase and follow up phase. Systemic allergic reactions included facial paralysis, flushing, hypersensitivity and rash pruritic. Injection related reactions were considered as systemic non-allergic reactions. Local site reactions included injection site bruising, erythema, pain and reaction. The analysis was performed on All treated Population which comprised of all participants that receive at least one dose of dabrafenib.
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [10] - All treated Population |
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No statistical analyses for this end point |
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End point title |
Number of participants with change from Baseline in clinical chemistry and hematology toxicity grades | ||||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected from participants for evaluation of change from Baseline in toxicity grades in clinical chemistry and hematology parameters. The clinical chemistry parameters included alkaline phosphatase, Alanine amino transferase (ALT), Aspartate amino transferase (AST), total bilirubin, creatinine, glucose, potassium, magnesium, sodium and phosphorus. The hematology parameters included hemoglobin, total neutrophils, platelets and white blood cells (WBC). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst-case post Baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [11] - All treated Population |
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No statistical analyses for this end point |
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End point title |
Number of participants with change from Baseline in temperature and pulse rate | ||||||||||||||||||
End point description |
Number of participants with change from Baseline in temperature and pulse rate were evaluated from the first dose of study treatment till discontinuation due to any reason. Change from Baseline in worst-case post Baseline value was presented as decrease to <=35, change to normal or no change and increase to >=38. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst case post-baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period.
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [12] - All treated Population |
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No statistical analyses for this end point |
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End point title |
Number of participants with increase from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) | ||||||||||||||
End point description |
Number of participants with increase from Baseline in SBP and DBP were evaluated from the first dose of study treatment till discontinuation due to any reason. Change from Baseline in worst-case post Baseline value was presented as any increase to >=80 and increase to >=100 for DBP and as any increase to >=120 and increase to >=160 for SBP. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst-case post Baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period.
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [13] - All treated Population |
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No statistical analyses for this end point |
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End point title |
Number of participants with change from Baseline in Left Ventricular Ejection Fraction (LVEF) levels | ||||||||||
End point description |
LVEF was defined as the percentage of blood pumped out of the left ventricle. Change from Baseline in worst-case post Baseline was presented as no change or any increase and any decrease values. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. The change from Baseline was calculated as visit value minus Baseline value and was presented in the form of worst-case post Baseline value which was the maximum toxicity grade for a participant after the first dose of study drug over the treatment period.
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End point type |
Secondary
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End point timeframe |
Up to 60 months
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Notes [14] - All treated Population |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of investigational product until death of all participants or a follow-up till 60 months.
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Adverse event reporting additional description |
SAEs and non-serious AEs were collected in the All Treated Participants Population, comprised of all randomized participants who received at least one dose of study medication, according to the actual treatment received.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
GSK2118436 150 mg
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Reporting group description |
Participants received GSK2118436 (gelatin capsules) 150 mg orally twice a day and continued on treatment until disease progression, death, or unacceptable AEs . Participants who are benefiting from GSK2118436 at the time of study completion will have the option to enter Study BRF114144 (NCT01231594), which is a rollover study for GSK2118436. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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23 Aug 2010 |
Country specific amendment for France to add valvular toxicity stopping criteria and to add that an Independent data monitoring committee (IDMC) will be established to review data from the study. |
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01 Sep 2010 |
Applies to all study sites. Modification of overall statistical design to include V600E mutant participants as the primary efficacy population and V600K in secondary efficacy assessments and updated primary and secondary objectives, endpoints, etc. accordingly; removal of V600D population; updates to First time in humans (FTIH) clinical activity and safety data and reference to the current version of the investigational brochure (IB); addition of IDMC to review data from interim analysis and periodically throughout the study; addition of valvular toxicity and Correction in QT interval (QTc) stopping criteria; changes to inclusion criteria to include treatment naïve participants and add computed tomography (CT) as a method for detecting brain metastases if magnetic resonance imaging (MRI) is contraindicated; deletion of exclusion criteria that excludes participants with a presence of rheumatoid arthritis, addition of exclusion criteria to exclude participants with history of alcohol or drug abuse within 6 months of screening and participants with known ocular or primary mucosal melanoma; changes to GSK2118436 storage temperature; modification of the frequency of efficacy assessments to every 8 weeks Week 20 to 52 and every 12 weeks from Week 52 until discontinuation; modifications to pregnancy section to address contraception requirements for female and male participants separately with a subsection on pregnancy; addition of mandatory cfDNA sample at discontinuation; addition of central reading of electrocardiogram (ECG) and Echocardiogram (ECHO)s; correction of minor typographical errors; administrative revisions to add/delete authors and update references. |
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14 Nov 2011 |
Footnote added to Table 4 Dose Modification that an ophthalmologic consultation is required if uveitis, blurry vision, eye pain, or erythema develops. A guideline for renal insufficiency was added for the management of renal toxicities; minor administrative change corrections; and correction of minor typographical errors. |
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19 Dec 2013 |
Updated study objectives to include secondary efficacy objective of long-term overall Survival; Updated definition of study completion throughout to allow for collection of long term survival data; Removed option for ongoing participants to transition to rollover study BRF114144 at the time of study completion; Updated dabrafenib dosing instructions; Updated dose modification guidelines for general toxicities and adverse events of special interest; Updated Liver Chemistry Stopping and Follow-up criteria to permit rechallenge/restart following liver toxicity; Updated permitted, prohibited and cautionary concomitant medication information; Updated treatment of dabrafenib overdose information; Updated visit schedule and dermatologic skin assessment frequency; As requested by the European Regulatory Authority, information for new malignancies will be collected throughout study treatment and follow-up; Removed male contraception requirement; As requested by French Regulatory Authority, additional monitoring following discontinuation of dabrafenib was incorporated; Minor administrative changes and typographical corrections throughout. |
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11 Mar 2014 |
Country specific amendment for Germany to incorporate additional monitoring for cutaneous squamous cell carcinoma, new primary melanoma and non-cutaneous secondary/recurrent malignancy at the request of the German Federal Institute for Drugs and Medical Devices (BfArM). |
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14 Sep 2015 |
Study will be closed out early. Reason for closure: As the primary endpoint of the study has been achieved and reported, (5 July 2012) it is believed that no significant new data or Overall Survival (OS) follow-up data will be generated in this study; Re-inserted the option for ongoing participants to transition to the roll-over study BRF114144 at the time of study completion or switch to commercially available Dabrafenib; FDA, EMA and other regulatory agencies approved dabrafenib for the treatment of participants with unresectable or metastatic melanoma with BRAF V600E mutation. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |