Clinical Trial Results:
A Phase III randomized, open-label study comparing GSK2118436 to DTIC in previously untreated subjects with BRAF mutation positive advanced (Stage III) or metastatic (Stage IV) melanoma.
Summary
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EudraCT number |
2009-015298-11 |
Trial protocol |
DE NL IE HU ES IT |
Global end of trial date |
16 Sep 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Sep 2017
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First version publication date |
22 Sep 2017
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Other versions |
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 |
113683
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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, +(1) 866-435-7343,
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Scientific contact |
GSK Response Center, GlaxoSmithKline, +(1) 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 |
19 Dec 2011
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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 |
16 Sep 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 for this study is to establish the superiority of GSK2118436 over DTIC with respect to progression-free survival for subjects with BRAF mutation positive metastatic melanoma
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Protection of trial subjects |
Not applicable
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Feb 2011
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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 |
Canada: 18
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Country: Number of subjects enrolled |
France: 36
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Country: Number of subjects enrolled |
Germany: 57
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Country: Number of subjects enrolled |
Hungary: 2
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Country: Number of subjects enrolled |
Australia: 16
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Country: Number of subjects enrolled |
Ireland: 4
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Country: Number of subjects enrolled |
Italy: 22
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Country: Number of subjects enrolled |
Netherlands: 8
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Country: Number of subjects enrolled |
Poland: 17
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Country: Number of subjects enrolled |
Russian Federation: 17
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Country: Number of subjects enrolled |
Spain: 21
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Country: Number of subjects enrolled |
United States: 32
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Worldwide total number of subjects |
250
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EEA total number of subjects |
167
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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) |
197
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From 65 to 84 years |
52
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85 years and over |
1
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Recruitment
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Recruitment details |
This was a Phase III randomized, open-label study to compare GSK2118436 to Dacarbazine (DTIC) in previously untreated participants (par.) with BRAF mutation positive advanced (Stage III) or metastatic (Stage IV) melanoma. This study was conducted at 70 centers in 12 countries. | |||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
The study has 2 phases: Randomized and Crossover Phase. In Randomized Phase, a total of 250 par. were randomized in 3:1 to receive either oral dabrafenib 150 mg twice daily (BID) or intravenous DTIC 1000 milligram/meter square. Par. in DTIC arm with disease progression were considered for crossover to dabrafenib arm in Crossover Phase | |||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Randomized Phase (RP)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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GSK2118436 150 mg BID | |||||||||||||||||||||||||||||||||
Arm description |
Participants (par.) were randomly assigned to receive oral GSK2118436 150 milligrams (mg) twice a day (BID). Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until disease progression (DP), death, the occurrence of an unacceptable adverse event (AE), or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
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) (50 mg x 3 capsules or 75 mg x 2 capsules) 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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Arm title
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DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase | |||||||||||||||||||||||||||||||||
Arm description |
In the RP, par. received intravenous (IV) Dacarbazine (DTIC) 1000 mg per meters squared (mg/m^2) every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Par. continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Par. who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Par. who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover par. continued on GSK2118436 until further DP was noted. After DP on GSK2118436, par. were followed for response, progression, survival, and further anti-cancer therapy. | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Dacarbazine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Dacarbazine 1000mg/m^2 was infused intravenously every 3 weeks.
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Period 2
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Period 2 title |
Crossover Phase
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Is this the baseline period? |
No | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
Arms
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Arm title
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DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase | |||||||||||||||||||||||||||||||||
Arm description |
In the RP, par. received intravenous (IV) Dacarbazine (DTIC) 1000 mg per meters squared (mg/m^2) every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Par. continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Par. who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Par. who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover par. continued on GSK2118436 until further DP was noted. After DP on GSK2118436, par. were followed for response, progression, survival, and further anti-cancer therapy. | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
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) (50 mg x 3 capsules or 75 mg x 2 capsules) 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 BID
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Reporting group description |
Participants (par.) were randomly assigned to receive oral GSK2118436 150 milligrams (mg) twice a day (BID). Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until disease progression (DP), death, the occurrence of an unacceptable adverse event (AE), or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase
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Reporting group description |
In the RP, par. received intravenous (IV) Dacarbazine (DTIC) 1000 mg per meters squared (mg/m^2) every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Par. continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Par. who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Par. who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover par. continued on GSK2118436 until further DP was noted. After DP on GSK2118436, par. were followed for response, progression, survival, and further anti-cancer therapy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
DTIC 1000 mg/m^2 in RP
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
In the RP, participants received intravenous (IV) Dacarbazine (DTIC) 1000 milligrams per meters squared (mg/m^2) every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.
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Subject analysis set title |
GSK25118436 in crossover phase
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Participants who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Participants who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover participants continued on GSK2118436 until further DP was noted. After DP on GSK2118436, participants were followed for response, progression, survival, and further anti-cancer therapy.
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Subject analysis set title |
All Screened Participants
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Specimens were tested for V600E mutations to determine trial eligibility with the CTA were retested with the THxID BRAF test. The analytical agreement between the THxID BRAF and the CTA was evaluated for both mutation positive and mutation negative specimens from all sites.
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End points reporting groups
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Reporting group title |
GSK2118436 150 mg BID
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Reporting group description |
Participants (par.) were randomly assigned to receive oral GSK2118436 150 milligrams (mg) twice a day (BID). Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until disease progression (DP), death, the occurrence of an unacceptable adverse event (AE), or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor. | ||
Reporting group title |
DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase
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Reporting group description |
In the RP, par. received intravenous (IV) Dacarbazine (DTIC) 1000 mg per meters squared (mg/m^2) every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Par. continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Par. who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Par. who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover par. continued on GSK2118436 until further DP was noted. After DP on GSK2118436, par. were followed for response, progression, survival, and further anti-cancer therapy. | ||
Reporting group title |
DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase
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Reporting group description |
In the RP, par. received intravenous (IV) Dacarbazine (DTIC) 1000 mg per meters squared (mg/m^2) every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Par. continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Par. who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Par. who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover par. continued on GSK2118436 until further DP was noted. After DP on GSK2118436, par. were followed for response, progression, survival, and further anti-cancer therapy. | ||
Subject analysis set title |
DTIC 1000 mg/m^2 in RP
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
In the RP, participants received intravenous (IV) Dacarbazine (DTIC) 1000 milligrams per meters squared (mg/m^2) every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.
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Subject analysis set title |
GSK25118436 in crossover phase
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Participants who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover participants continued on GSK2118436 until further DP was noted. After DP on GSK2118436, participants were followed for response, progression, survival, and further anti-cancer therapy.
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Subject analysis set title |
All Screened Participants
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Specimens were tested for V600E mutations to determine trial eligibility with the CTA were retested with the THxID BRAF test. The analytical agreement between the THxID BRAF and the CTA was evaluated for both mutation positive and mutation negative specimens from all sites.
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End point title |
Progression-free Survival (PFS) as assessed by the Investigator [1] | |||||||||||||||
End point description |
PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). For participants who did not progress or die,PFS was censored at the date of last contact. Data are presented as median and 96% confidence interval.Intent-to-Treat (ITT) Population: all randomized participants whether or not treatment was administered
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End point type |
Primary
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End point timeframe |
Time interval between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause (up to 9.9 months)
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Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period. |
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Notes [2] - Intent-to-Treat (ITT) Population: all randomized participants regardless of whether or not treatment |
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Statistical analysis title |
Statistical analysis 1 | |||||||||||||||
Statistical analysis description |
HRs were estimated using a Pike estimator. HR from a stratified log-rank test was adjusted for disease stage at screening.
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Comparison groups |
GSK2118436 150 mg BID v DTIC 1000 mg/m^2 in RP
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Number of subjects included in analysis |
250
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
< 0.0001 [3] | |||||||||||||||
Method |
Logrank | |||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||
Point estimate |
0.4
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.26 | |||||||||||||||
upper limit |
0.6 | |||||||||||||||
Notes [3] - The p value from a stratified log-rank test was adjusted for disease stage at screening. |
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End point title |
Progression-free Survival (PFS) as assessed by an Independent Radiologist: Randomized Phase [4] | |||||||||||||||
End point description |
PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by an independent radiologist according to RECIST version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact.
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End point type |
Primary
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End point timeframe |
Time interval between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause (up to 9.9 months)
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Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period. |
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Notes [5] - ITT Population |
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Statistical analysis title |
Statistical analysis 1 | |||||||||||||||
Statistical analysis description |
HRs were estimated using a Pike estimator. HR from a stratified log-rank test was adjusted for disease stage at screening.
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Comparison groups |
GSK2118436 150 mg BID v DTIC 1000 mg/m^2 in RP
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Number of subjects included in analysis |
250
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
Method |
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Parameter type |
Hazard ratio (HR) | |||||||||||||||
Point estimate |
0.35
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.2 | |||||||||||||||
upper limit |
0.61 |
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End point title |
Overall survival [6] | |||||||||||||||
End point description |
Overall survival is defined as the interval of time between the date of randomization and the date of death due to any cause. For participants who did not die, overall survival was censored at the date of last contact.
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End point type |
Secondary
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End point timeframe |
Time interval between the date of randomization and the date of death due to any cause (up to 22.1 months)
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Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period. |
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Notes [7] - ITT Population |
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Statistical analysis title |
Statistical analysis 1 | |||||||||||||||
Statistical analysis description |
HRs were estimated using a Pike estimator. HR was adjusted for disease stage at screening.
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Comparison groups |
GSK2118436 150 mg BID v DTIC 1000 mg/m^2 in RP
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Number of subjects included in analysis |
250
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
Method |
||||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||
Point estimate |
0.82
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
0.57 | |||||||||||||||
upper limit |
1.18 |
|
||||||||||||||||
End point title |
Number of participants with a best overall response of confirmed complete response (CR) or confirmed partial response (PR) as assessed by the Investigator: Randomized Phase [8] | |||||||||||||||
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% 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]). Response was evaluated by an investigator per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From randomization until the first documented evidence of a confirmed complete response or partial response (median of 6.6 weeks)
|
|||||||||||||||
Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period. |
||||||||||||||||
|
||||||||||||||||
Notes [9] - ITT Population |
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of participants with a best overall response of confirmed CR or PR as assessed by an Independent Radiologist: Randomized Phase [10] | |||||||||||||||
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% 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]). Response was evaluated by an independent radiologist per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From randomization until the first documented evidence of a confirmed complete response or partial response (median of 12.0 weeks)
|
|||||||||||||||
Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period. |
||||||||||||||||
|
||||||||||||||||
Notes [11] - ITT Population |
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Duration of Response as assessed by the Investigator: Randomized Phase [12] | |||||||||||||||
End point description |
Duration of response for participants with 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% 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]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 65.6 weeks)
|
|||||||||||||||
Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period. |
||||||||||||||||
|
||||||||||||||||
Notes [13] - ITT Population. Only participants with a confirmed CR or PR were assessed for duration of response. |
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Duration of Response as assessed by an Independent Radiologist: Randomized Phase [14] | |||||||||||||||
End point description |
Duration of response for participants with 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% 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]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. 99999 indicates that data is not available.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 7.4 months)
|
|||||||||||||||
Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period. |
||||||||||||||||
|
||||||||||||||||
Notes [15] - ITT Population. Only participants with a confirmed CR or PR were assessed for duration of response. |
||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||
End point title |
Progression-free Survival (PFS2) as assessed by the Investigator: Crossover Phase | ||||||||||
End point description |
PFS2 is defined as the time from the first dose of GSK2118436, in participants randomized to DTIC who crossed over to GSK2118436 after initial progression, to the earliest date of radiographic or photographic disease progression or death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact. Crossover Treatment Population: participants who were randomized to DTIC arm, and elected to receive GSK2118436
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Time from first dose of GSK2118436 in participants who crossover after initial progression to the earliest date of radiographical or photographical PD or death due to any cause (up to 6.4 months)
|
||||||||||
|
|||||||||||
Notes [16] - Crossover Treatment Population: Only participants who received at least one dose of GSK2118436 |
|||||||||||
No statistical analyses for this end point |
|
|||||||||||
End point title |
Number of participants with a best overall response of confirmed complete response (CR) or confirmed partial response (PR) as assessed by the Investigator: Crossover Phase | ||||||||||
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% 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]). Response was evaluated by an investigator per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
From randomization until the first documented evidence of a confirmed complete response or partial response (up to 6.4 months)
|
||||||||||
|
|||||||||||
Notes [17] - Crossover Treatment Population |
|||||||||||
No statistical analyses for this end point |
|
|||||||||||
End point title |
Duration of Response as assessed by the Investigator: Crossover Phase | ||||||||||
End point description |
Duration of response for participants with 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% 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]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Crossover Population: Only participants with a confirmed CR or PR were assessed for duration of response.
|
||||||||||
End point type |
Secondary
|
||||||||||
End point timeframe |
Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 6.4 months)
|
||||||||||
|
|||||||||||
Notes [18] - Crossover Treatment Population. |
|||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of participants with non-melanoma skin lesions: Randomized Phase [19] | |||||||||||||||
End point description |
Dermatological examinations were performed by the investigator, or at the discretion of the investigator, referred to a dermatologist. The number of participants with non-melanoma skin lessions was assessed from the time of Screening until study completion or discontinuation from the study for any reason.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From Screening until study completion or discontinuation from the study (up to 9.9 months)
|
|||||||||||||||
Notes [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period. |
||||||||||||||||
|
||||||||||||||||
Notes [20] - Safety Population: all randomized participants who received at least one dose of study drug |
||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Agreement rate for V600E mutation validation of the BRAF mutation assay | ||||||||||||||||
End point description |
Analytical and clinical validation of the companion diagnostic (cDx) assay was performed to determine the extent of agreement between the bioMerieux cDx assay (THxID BRAF Assay) and the Clinical Trial Assay (CTA) to detect BRAF mutations to determine participant eligibility into the study. Skin tissue samples collected at the Screening visit were used for this analysis. Multiple specimen per participant were analyzed.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Screening
|
||||||||||||||||
|
|||||||||||||||||
Notes [21] - V600E positive participants screened for BREAK-3 study |
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of investigational product to the end of the study. The total duration of the study including a long-term follow-up phase was up to 5 years.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study drug, based on the actual treatment received, if this differed from that to which the participant was randomized.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
|
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Reporting groups
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Reporting group title |
GSK2118436 150 mg BID
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Reporting group description |
Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
DTIC 1000 mg/m^2 in RP
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Reporting group description |
In the RP, participants received IV DTIC 1000 mg/m^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
GSK25118436 in the Crossover Phase
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Reporting group description |
Participants who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Participants who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover participants continued on GSK2118436 until further DP was noted. After DP on GSK2118436, participants were followed for response, progression, survival, and further anti-cancer therapy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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03 Nov 2010 |
Amendment No. 01: This amendment modified the contraception section based upon additional non-clinical toxicology results; added a computed tomography scan for respiratory symptoms within the dose modification guidelines table corrected typographical errors in the statistics section; added assessment of secondary malignancies to the secondary safety objectives; added evaluation of Health-Related Quality of Life (HRQOL) parameters for participants who crossover to dabrafenib from randomized treatment with DTIC following initial progression; and changed the collection requirements for a Circulating cell-free DNA (cfDNA) sample at progression from optional to mandatory. |
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04 Mar 2011 |
Amendment No. 02: It was a country specific amendment for France to modify the QTc stopping criteria in response to a request from the French regulatory agency, AFSSAPS |
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23 Mar 2011 |
Amendment No. 03: This amendment added the collection of serial pharmacokinetics (PK) samples in a subset of participants to further characterize final dabrafenib formulation; clarified crossover eligibility criteria; included administrative corrections to Time and Events tables and specifically clarified timing of assessments; modified the tumor tissue requirements to allow primary tissue for screening; clarified QOL time points and modified data collection instructions to allow 1 questionnaire to be completed via phone; and added best ORR as a secondary efficacy objective. |
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03 Jun 2011 |
Amendment No. 04: This amendment updated the dose monitoring and management guidelines for neutropenia and fever based on emerging safety data from other ongoing dabrafenib studies; added wording to allow the collection of non-melanoma skin biopsy slides and pathology reports; changed the collection of full body skin photos at baseline from required to recommended; clarified the Safety and QOL endpoints; added wording to recommend PK collection for all serious adverse events; included administrative corrections and added a Day 8 absolute neutrophil count. Dexamethasone was added to the cautionary medications section. |
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14 Nov 2011 |
Amendment No. 05: This amendment added a treatment option that allowed participants with investigator reported disease progression who were still benefitting from study treatment with dabrafenib to continue study drug. Also added new guidelines for the management of renal insufficiency and new criteria for dose modifications related to grade 3 toxicities. |
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20 Apr 2012 |
Amendment No. 06: The results of the planned primary analysis confirmed that the primary endpoint of improved progression free survival in the dabrafenib (dabrafenib arm) was achieved. The data was reviewed with the IDMC and the committee unanimously recommended that participants who were randomized to the DTIC arm of the study be allowed the option to receive dabrafenib prior to disease progression based on the judgment of the investigator. Independent review confirmation of disease progression will no longer be prior to crossover. The crossover rules were updated. Time and Events Table 13 was updated with requirement for re-establishing efficacy and safety baseline measures within 28 days of first dose of dabrafenib and QOL requirement at crossover was clarified. Statistics section updated to reflect the new analyses plans and to address multiple testing issues. Wording was modified in the safety section to clarify intent in the collection of events of pyrexia and basal cell carcinoma. |
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19 Feb 2014 |
Amendment No. 07: Major updates include changes to secondary objectives and study design; study closure at 70% of deaths was removed and updated to follow participants to estimate long-term OS (particularly 5 years in treatment groups). Definition to permanent discontinuation was updated to clarify that all participants were to be followed to death or until lost to follow up. Study completion was changed to collect long-term (5 years), overall survival.
The other key changes include updates to Adverse Events of Special Interest (AESIs) and dose modification to reflect latest label language: Dose Modification Guidelines for AESI are updated; Neutropenia was removed from the list; QTc updated to align with French Guidelines for reporting; Liver chemistry monitoring, management and restarting treatment conditions were updated; Secondary analysis updated to reflect long-term OS estimates; Appendix added for French specific skin monitoring guidelines. |
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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 |