A Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Crossover Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Cancer
Interventions:	Drug: GSK2118436 Drug: Dacarbazine (DTIC)

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
In the Randomized Phase, participants receiving GSK2118436 150 milligrams were treated for up to 16.4 months, and participants receiving dacarbazine 1000 milligrams per meters squared were treated for up to 12.2 months.

Reporting Groups

	Description
GSK2118436 150 mg BID	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.
DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase	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.

Description

GSK2118436 150 mg BID

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.

DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase

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.

Participant Flow for 2 periods

Period 1: Randomized Phase (RP)

	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase
STARTED	187	63
In Follow-up	49	10
Ongoing	53	2
Crossed Over	0	36
COMPLETED	0	0
NOT COMPLETED	187	63
Lost to Follow-up	3	1
Physician Decision	2	1
Withdrawal by Subject	2	5
Death	78	8
Crossed Over	0	36
Ongoing	53	2
In Follow-up	49	10

Period 2: Crossover Phase

	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase
STARTED	0	36 ^[1]
In Follow-up	0	11
Ongoing	0	4
COMPLETED	0	0
NOT COMPLETED	0	36
Withdrawal by Subject	0	1
Death	0	20
Ongoing	0	4
In Follow-up	0	11

[1]	As of the data cut on December 18, 2012, 36 of 63 participants crossed over from DTIC to GSK2118436.

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
GSK2118436 150 mg BID	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.
DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase	In the RP, par. 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. 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.
Total	Total of all reporting groups

Baseline Measures

	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase	Total
Number of Participants [units: participants]	187	63	250
Age [units: Years] Mean (Standard Deviation)	53.5 (13.76)	51.6 (14.22)	53.0 (13.87)
Gender [units: Participants]
Female	75	26	101
Male	112	37	149
Race/Ethnicity, Customized [units: participants]
White	186	63	249
Missing	1	0	1

Outcome Measures

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1. Primary:

Progression-free Survival (PFS) as Assessed by the Investigator [ Time Frame: 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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2. Primary:

Progression-free Survival (PFS) as Assessed by an Independent Radiologist [ Time Frame: 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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3. Secondary:

Overall Survival [ Time Frame: 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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4. Secondary:

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 [ Time Frame: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 6.6 weeks) ]

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5. Secondary:

Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase [ Time Frame: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 12.0 weeks) ]

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6. Secondary:

Duration of Response as Assessed by the Investigator: Randomized Phase [ Time Frame: 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) ]

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7. Secondary:

Duration of Response as Assessed by an Independent Radiologist: Randomized Phase [ Time Frame: 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) ]

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8. Secondary:

Progression-free Survival (PFS2) as Assessed by the Investigator: Crossover Phase [ Time Frame: 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) ]

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9. Secondary:

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 [ Time Frame: From randomization until the first documented evidence of a confirmed complete response or partial response (up to 6.4 months) ]

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10. Secondary:

Duration of Response as Assessed by the Investigator: Crossover Phase [ Time Frame: 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) ]

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11. Secondary:

Number of Participants With Non-melanoma Skin Lesions: Randomized Phase [ Time Frame: From Screening until study completion or discontinuation from the study (up to 9.9 months) ]

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12. Secondary:

Validation of the BRAF Mutation Assay [ Time Frame: Screening ]

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact:

Name/Title: GSK Response Center
Organization: GlaxoSmithKline
phone: 866-435-7343

Publications:

Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Santiago-Walker A, Gagnon R, Mazumdar J, Casey M, Long GV, Schadendorf D, Flaherty K, Kefford R, Hauschild A, Hwu P, Haney P, O'Hagan A, Carver J, Goodman V, Legos J, Martin AM. Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials. Clin Cancer Res. 2016 Feb 1;22(3):567-74. doi: 10.1158/1078-0432.CCR-15-0321. Epub 2015 Oct 7.

Latimer NR, Abrams KR, Amonkar MM, Stapelkamp C, Swann RS. Adjusting for the Confounding Effects of Treatment Switching-The BREAK-3 Trial: Dabrafenib Versus Dacarbazine. Oncologist. 2015 Jul;20(7):798-805. doi: 10.1634/theoncologist.2014-0429. Epub 2015 Jun 3.

Grob JJ, Amonkar MM, Martin-Algarra S, Demidov LV, Goodman V, Grotzinger K, Haney P, Kämpgen E, Karaszewska B, Mauch C, Miller WH Jr, Millward M, Mirakhur B, Rutkowski P, Chiarion-Sileni V, Swann S, Hauschild A. Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine. Ann Oncol. 2014 Jul;25(7):1428-36. doi: 10.1093/annonc/mdu154. Epub 2014 Apr 25.

Ouellet D, Gibiansky E, Leonowens C, O'Hagan A, Haney P, Switzky J, Goodman VL. Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites. J Clin Pharmacol. 2014 Jun;54(6):696-706. doi: 10.1002/jcph.263. Epub 2014 Jan 17.

Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT01227889 History of Changes
Other Study ID Numbers:	113683
Study First Received:	October 21, 2010
Results First Received:	June 6, 2013
Last Updated:	July 18, 2016
Health Authority:	Italy: AIFA - Italian Ministry of Health France: Ministry of Health Italy: Comitato Etico Fondazione Centro San Raffaele del Monte Tabor - Via Olgettina, 60 - 20132 Milano Canada: Health Canada Hungary: National Institute of Pharmacy Spain: Ministry of Health and Consumption Ireland: Irish Medicines Board United States: Food and Drug Administration Russia: Russian Ministry of Health Poland: Ministry of Health Germany: Bundesinstitut für Arzneimittel und Medizinprodukte Netherlands: Medical Ethics Review Committee (METC) Australia: Therapeutic Goods Administration