Study to Investigate the Objective Response Rate of Dabrafenib in Combination With Trametinib in Subjects With BRAF V600 Mutation-Positive Melanoma

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02083354
• Collaborator: (none)
• Enrollment: 77
• Locations: 13
• Arm: 1
• Actual Duration (Months): 85.1
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a single-arm, open-label, multi-center, Phase II study to evaluate dabrafenib and trametinib combination therapy in subjects with BRAF V600 mutation-positive, unresectable or metastatic Acral lentiginous or cutaneous melanoma. This study evaluated the objective response rate (ORR), progression free survival (PFS), duration of response, overall survival (OS), safety and efficacy, to assess steady state (all subjects) exposure to dabrafenib, dabrafenib metabolites, and trametinib and characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of dabrafenib and trametinib. Enrolled subjects were administered dabrafenib 150 milligram (mg) orally twice daily and trametinib 2 mg orally once daily. Treatment continued until disease progression, death, unacceptable toxicity, or withdrawal of consent, or study closure. After treatment discontinuation, subjects were followed for survival and disease progression as applicable.

Condition or Disease	Intervention/Treatment	Phase
Cancer; Melanoma	Drug: Dabrafenib; Drug: Trametinib	Phase 2

Detailed Description

This was an open-label, single arm, Phase IIA, multi-center study to evaluate the Objective response rate (ORR) of dabrafenib and trametinib combination therapy in East Asian subjects that have BRAF V600 mutationpositive Stage IIIC (unresectable) or Stage IV (metastatic) acral lentiginous melanoma (ALM) or cutaneous melanoma.

All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. A primary analysis presented the efficacy, safety and pharmacokinetics (PK) data up to the data cut-off date of 23-Feb-2018. Based on these results, dabrafenib and trametinib combination was approved in the People's Republic of China (PRC) for the treatment of BRAF-mutation positive unresectable or metastatic melanoma. Data from Mainland Chinese subjects from 01-Jul-2019 onwards are not included due to local regulations in China.

Subjects continued study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study completion. After treatment discontinuation, subjects went into follow-up for survival and disease progression as applicable. Subjects could continue study treatment after disease progression if they achieved clinical response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or stable disease with tumour reduction; had no overt signs of toxicity; had Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 and did not require immediate surgical or radiological intervention.

Study Design

• Study Type: Interventional
• Actual Enrollment: 77 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Center Study to Investigate the Objective Response Rate of Dabrafenib in Combination With Trametinib in Subjects With BRAF V600 Mutation-Positive Melanoma
• Actual Study Start Date: Mar 18, 2014
• Actual Primary Completion Date: Feb 23, 2018
• Actual Study Completion Date: Apr 19, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Arm 1 All subjects will receive the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone will be administered approximately 12 hours after the morning dose. Subjects will continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure

Drug: Dabrafenib; Dabrafenib will be provided as 50 mg and 75 mg capsules. Each capsule will contain 50 mg or 75 mg of free base (present as the mesylate salt); Drug: Trametinib; Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets. Each tablet will contain 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) [Up to 35 months]

   To determine ORR of dabrafenib in combination with trametinib in subjects with BRAF V600 mutation-positive, unresectable or metastatic melanoma. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by the investigator.

Secondary Outcome Measures

1. Progression-free Survival (PFS) - Median [Up to 36 months]

   PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause

2. Progression-free Survival (PFS) [Up to 36 months]

   PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.

3. Duration of Response (DOR) - Estimate for Duration of Response - Median [Up to 36 months]

   Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR.

4. Duration of Response (DOR) [Up to 36 months]

   Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.

5. Overall Survival (OS) - Median [Approximately 5 years]

   OS is defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact

6. Overall Survival (OS) [Approximately 5 years]

   OS is defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.

7. Number of Participants With Adverse Events [Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 51 months (for both dabrafenib and also Rametinib).]

   An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

8. Population Pharmacokinetics of Dabrafenib - Cmax [Day 1 and Day 15]

   Cmax is the maximum peak concentration.

9. Population Pharmacokinetics of Dabrafenib - Tmax [Day 1 and Day 15]

   Tmax is Time to Cmax (maximum peak concentration).

10. Population Pharmacokinetics of Dabrafenib - AUC(0-12) [Day 1 and Day 15]

    AUC is the area under the concentration-time curve.

11. Population Pharmacokinetics of Dabrafenib - Ctrough [Day 1 and Day 15]

    Ctrough is trough concentration.

12. Population Pharmacokinetics of Dabrafenib - Racc [Day 1 and Day 15]

    Racc is the accumulation ratio.

13. Population Pharmacokinetics of Hydroxydabrafenib - Cmax [Day 1 and Day 15]

    Cmax is the maximum peak concentration.

14. Population Pharmacokinetics of Hydroxydabrafenib - Tmax [Day 1 and Day 15]

    Tmax is Time to Cmax (maximum peak concentration).

15. Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12) [Day 1 and Day 15]

    AUC is the area under the concentration-time curve.

16. Population Pharmacokinetics of Hydroxydabrafenib - Rm/p [Day 1 and Day 15]

    Rm/p is the metabolite-to-parent ratio.

17. Population Pharmacokinetics of Hydroxydabrafenib - Ctrough [Day 1 and Day 15]

    Ctrough is trough concentration.

18. Population Pharmacokinetics of Hydroxydabrafenib - Racc [Day 1 and Day 15]

    Racc is the accumulation ratio.

19. Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax [Day 1 and Day 15]

    Cmax is the maximum peak concentration.

20. Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax [Day 1 and Day 15]

    Tmax is Time to Cmax (maximum peak concentration).

21. Population Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12) [Day 1 and Day 15]

    AUC is the area under the concentration-time curve. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib.

22. Population Pharmacokinetics of Desmethyl-dabrafenib - Rm/p [Day 1 and Day 15]

    Rm/p is the metabolite-to-parent ratio. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib.

23. Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough [Day 1 and Day 15]

    Ctrough is trough concentration.

24. Population Pharmacokinetics of Carboxydabrafenib - Cmax [Day 1 and Day 15]

    Cmax is the maximum peak concentration.

25. Population Pharmacokinetics of Carboxydabrafenib - Tmax [Day 1 and Day 15]

    Tmax is Time to Cmax (maximum peak concentration).

26. Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12) [Day 1 and Day 15]

    AUC is the area under the concentration-time curve.

27. Population Pharmacokinetics of Carboxydabrafenib - Rm/p [Day 1 and Day 15]

    Rm/p is the metabolite-to-parent ratio.

28. Population Pharmacokinetics of Carboxydabrafenib - Ctrough [Day 1 and Day 15]

    Ctrough is trough concentration.

29. Population Pharmacokinetics of Carboxydabrafenib - Racc [Day 1 and Day 15]

    Racc is the accumulation ratio.

30. Population Pharmacokinetics of Trametinib - Cmax [Day 1 and Day 15]

    Cmax is the maximum peak concentration.

31. Population Pharmacokinetics of Trametinib - Tmax [Day 1 and Day 15]

    Tmax is Time to Cmax (maximum peak concentration).

32. Population Pharmacokinetics of Trametinib - AUC(0-t) [Day 1 and Day 15]

    Area under the concentration-time curve from time zero (predose) to last time of quantifiable concentration within a subject across all treatments

33. Population Pharmacokinetics of Trametinib - AUC(0-24) [Day 1 and Day 15]

    AUC is the area under the concentration-time curve.

34. Population Pharmacokinetics of Trametinib - Ctrough [Day 1 and Day 15]

    Ctrough is trough concentration.

35. Population Pharmacokinetics of Trametinib - Racc [Day 1 and Day 15]

    Racc is the accumulation ratio.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

• =18 years of age.

• Histologically confirmed acral lentiginous or cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and BRAF V600 mutation-positive. The test was to have been conducted at a designated central laboratory.

• Measurable disease (i.e., present with at least one measurable lesion) by RECIST version1.1.

• Performance status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.

• All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values) must be <=Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of enrolment.

• Able to swallow and retain oral medication and must not have had any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.

• Women of child-bearing potential must have had a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception, from 14 days prior to enrolment, throughout the treatment period and for 4 months after the last dose of study treatment.

• Adequate baseline organ function as defined below: Absolute Neutrophil Count:>= 1.2 × 10^{9/liter (L); Hemoglobin: >=9 grams (g)/deciliter (dL); Platelet count: >=100 x 10}9/L; Prothrombin Time/International Normalized Ratio (INR) (Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to enrolment) and Partial Thromboplastin Time: <=1.5 x Upper Limit of Normal (ULN); Albumin: >=2.5 g/dL; Total bilirubin: <=1.5 x ULN; Aspartate aminotransferase and Alanine aminotransferase: <=2.5 x ULN; Calculated creatinine clearance (Calculate creatinine clearance using standard Cockcroft-Gault formula): >=50 milliliter (mL)/ minute (min); Left Ventricular Ejection Fraction (LVEF) (ECHO scans must be used throughout the study) : >= Lower limit of normal (LLN) by ECHO.

• Subjects with East Asian origin.

Exclusion Criteria:

• Primary mucosal or ocular melanoma.

• Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119).

• Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic anti-cancer therapy, or immuno anti-cancer therapy within 21 days prior to enrolment /or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrolment. (Note: Ipilimumab, pembrolizumab and nivolumab treatment must ended at least 8 weeks prior to enrollment).

• Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to enrolment. (Note: in case ipilimuamb, pembrolizmab and nivolumab are investigational drug in the regions and countries, and in case of PD-L1 antibody, these investigational treatment must have ended at least 8 weeks prior to enrollment ).

• Current use of a prohibited medication.

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).

• A history of Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted).

• Leptomeningeal or brain metastases or metastases causing spinal cord compression that were: symptomatic or untreated or not stable for 3 months (must be documented by imaging) or requiring corticosteroids. Subjects that were on a stable dose of corticosteroids >1 month or on replacement dose only, or have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the medical monitor. Subjects must also have been off of enzyme-inducing anticonvulsants for >4 weeks.

• History of malignancy other than disease under study within 3 years of study enrolment with exceptions of subjects with a history of completely resected non-melanoma skin cancer, or subjects with indolent second malignancies were eligible only after the approval of the sponsor's medical monitor.

• History of malignancy with confirmed activating RAS mutation at any time. Note: Prospective RAS testing was not required. However, if the results of previous RAS testing were known, they must have been used in assessing eligibility

• Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could have interfered with the subject's safety, obtaining informed consent, or compliance with study procedures.

• A history or evidence of cardiovascular risk including any of the following: Current LVEF < Institutional LLN; A QTc interval corrected for heart rate >=480 millisecond (msec) (using Bazett's formula); A history or evidence of current clinically significant uncontrolled arrhythmias. Clarification: Subjects with atrial fibrillation controlled for >30 days prior to dosing are eligible; A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; A history or evidence of current

=Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; Patients with intra-cardiac defibrillators; Treatment refractory hypertension defined as a blood pressure of systolic >140 millimeters of mercury (mmHg) and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy; Known cardiac metastases; Abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not have been entered in study.

• Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia determined by blood chemistry), long QT syndrome or taking medicinal products known to prolong the QT interval.

• A history or current evidence of retinal vein occlusion (RVO) .

• Pregnant or nursing females.

• History of or current diagnosis of interstitial lung disease or pneumonitis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Guangzhou	Guangdong	China	510060
2	Novartis Investigative Site	Kunming	Yunnan	China	650106
3	Novartis Investigative Site	Hangzhou	Zhejiang	China	310022
4	Novartis Investigative Site	Beijing		China	100036
5	Novartis Investigative Site	Tuen Mun		Hong Kong
6	Novartis Investigative Site	Seoul		Korea, Republic of	110-744
7	Novartis Investigative Site	Seoul		Korea, Republic of	120-752
8	Novartis Investigative Site	Kaohsiung		Taiwan	807
9	Novartis Investigative Site	Taipei		Taiwan	100
10	Novartis Investigative Site	Taoyuan		Taiwan	333
11	Novartis Investigative Site	Bangkok		Thailand	10320
12	Novartis Investigative Site	Bangkok		Thailand	10400
13	Novartis Investigative Site	Songkla		Thailand	90110

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Nov 27, 2019
• Statistical Analysis Plan - May 5, 2021

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02083354
• Other Study ID Numbers: 200104; CDRB436B2205
• First Posted: Mar 11, 2014
• Last Update Posted: Feb 1, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: melanoma; dabrafenib; trametinib; malignant skin cancer; skin cancer; BRAF V600 Mutation-Positive Melanoma
• Additional relevant MeSH terms: Melanoma; Trametinib; Dabrafenib

Study Results

Participant Flow

Pre-assignment Detail	77 participants were enrolled in the study.

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Period Title: Overall Study
STARTED	77
COMPLETED	13
NOT COMPLETED	64

Baseline Characteristics

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Overall Participants	77
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.6 (13.08)
Sex: Female, Male (Count of Participants)
Female	42 54.5%
Male	35 45.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	77 100%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	To determine ORR of dabrafenib in combination with trametinib in subjects with BRAF V600 mutation-positive, unresectable or metastatic melanoma. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by the investigator.
Time Frame	Up to 35 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	77
Number (95% Confidence Interval) [Percentage of Participants]	61 79.2%

2. Secondary Outcome

Title	Progression-free Survival (PFS) - Median
Description	PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	77
Median (95% Confidence Interval) [months]	9.17

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	77
Progressive Disease (PD) (event)	52 67.5%
Died (event)	4 5.2%
Censored, follow-up ended	10 13%
Censored, follow-up ongoing	11 14.3%

4. Secondary Outcome

Title	Duration of Response (DOR) - Estimate for Duration of Response - Median
Description	Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

Full analysis set, for participants who achieved CR or PR.

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	48
Median (95% Confidence Interval) [Months]	12.65

5. Secondary Outcome

Title	Duration of Response (DOR)
Description	Duration of response is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until the earliest date of documented radiological progression or death due to any cause among subjects who achieved a confirmed CR or PR. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	48
PFS - Disease Progression	27 35.1%
PFS - Death	2 2.6%
PFS - Censored, follow-up ended	9 11.7%
PFS - Censored, follow-up ongoing	10 13%

6. Secondary Outcome

Title	Overall Survival (OS) - Median
Description	OS is defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact
Time Frame	Approximately 5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	77
Median (95% Confidence Interval) [Months]	22.90

7. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact. Censored, follow-up ongoing - These subjects show as ongoing in the clinical database even though no subjects are currently ongoing, as no changes to the data were permitted after 30-Jun-2019 due to local regulations in China.
Time Frame	Approximately 5 years

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	77
Died (Event)	43 55.8%
Censored, follow-up ended	13 16.9%
Censored, follow-up ongoing	21 27.3%

8. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Time Frame	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 51 months (for both dabrafenib and also Rametinib).

Outcome Measure Data

Analysis Population Description

Safety set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	77
Adverse events - all grades	76 98.7%
Adverse events - Treatment-related - all grades	69 89.6%
SAEs - all grades	18 23.4%
SAEs - Treatment-related - all grades	9 11.7%
Fatal SAEs - all grades	4 5.2%
Fatal SAEs - Treatment-related - all grades	1 1.3%
AEs leading to discontinuation - all grades	6 7.8%
AEs leading to discontinuation - Treatment-related - all grades	3 3.9%
AEs leading to dose adjustment/interruption - all grades	39 50.6%
AEs leading to dose reduction - all grades	23 29.9%

9. Secondary Outcome

Title	Population Pharmacokinetics of Dabrafenib - Cmax
Description	Cmax is the maximum peak concentration.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	2950 (72.8)
Day 15 (n=18)	2300 (70.6)

10. Secondary Outcome

Title	Population Pharmacokinetics of Dabrafenib - Tmax
Description	Tmax is Time to Cmax (maximum peak concentration).
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	1.95
Day 15 (n=18)	1.5

11. Secondary Outcome

Title	Population Pharmacokinetics of Dabrafenib - AUC(0-12)
Description	AUC is the area under the concentration-time curve.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Day 1	11400 (46.1)
Day 15	6600 (55.6)

12. Secondary Outcome

Title	Population Pharmacokinetics of Dabrafenib - Ctrough
Description	Ctrough is trough concentration.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	77 (84.3)

13. Secondary Outcome

Title	Population Pharmacokinetics of Dabrafenib - Racc
Description	Racc is the accumulation ratio.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	14
Geometric Mean (Geometric Coefficient of Variation) [ratio]	0.624 (42.7)

14. Secondary Outcome

Title	Population Pharmacokinetics of Hydroxydabrafenib - Cmax
Description	Cmax is the maximum peak concentration.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	1230 (44.1)
Day 15 (n=18)	1200 (58.7)

15. Secondary Outcome

Title	Population Pharmacokinetics of Hydroxydabrafenib - Tmax
Description	Tmax is Time to Cmax (maximum peak concentration).
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	3.08
Day 15 (n=18)	1.96

16. Secondary Outcome

Title	Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12)
Description	AUC is the area under the concentration-time curve.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Day 1 (n=17)	7930 (43)
Day 15	4440 (43.4)

17. Secondary Outcome

Title	Population Pharmacokinetics of Hydroxydabrafenib - Rm/p
Description	Rm/p is the metabolite-to-parent ratio.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Day 1 (n=17)	0.68 (17)
Day 15	0.653 (21.4)

18. Secondary Outcome

Title	Population Pharmacokinetics of Hydroxydabrafenib - Ctrough
Description	Ctrough is trough concentration.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	94 (61.9)

19. Secondary Outcome

Title	Population Pharmacokinetics of Hydroxydabrafenib - Racc
Description	Racc is the accumulation ratio.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	13
Geometric Mean (Geometric Coefficient of Variation) [ratio]	0.56 (35.5)

20. Secondary Outcome

Title	Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax
Description	Cmax is the maximum peak concentration.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	48.9 (93.5)
Day 15 (n=18)	466 (51.6)

21. Secondary Outcome

Title	Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax
Description	Tmax is Time to Cmax (maximum peak concentration).
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	9.9
Day 15 (n=18)	2.48

22. Secondary Outcome

Title	Population Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12)
Description	AUC is the area under the concentration-time curve. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Geometric Mean (Geometric Coefficient of Variation) [h.ng/mL]	3960 (52.9)

23. Secondary Outcome

Title	Population Pharmacokinetics of Desmethyl-dabrafenib - Rm/p
Description	Rm/p is the metabolite-to-parent ratio. AUC0-12 and Rm/p could not be calculated on Day 1 because all desmethyl-dabrafenib PK profiles on Day 1 were still ascending. Therefore, the Racc on Day 15 could not be calculated for desmethyldabrafenib.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Geometric Mean (Geometric Coefficient of Variation) [ratio]	0.616 (51.4)

24. Secondary Outcome

Title	Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough
Description	Ctrough is trough concentration.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	365 (63.7)

25. Secondary Outcome

Title	Population Pharmacokinetics of Carboxydabrafenib - Cmax
Description	Cmax is the maximum peak concentration.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	3760 (75.7)
Day 15 (n=18)	9750 (32.8)

26. Secondary Outcome

Title	Population Pharmacokinetics of Carboxydabrafenib - Tmax
Description	Tmax is Time to Cmax (maximum peak concentration).
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	8.94
Day 15 (n=18)	3.5

27. Secondary Outcome

Title	Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12)
Description	AUC is the area under the concentration-time curve.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Day 1 (n=1)	34400 (NA)
Day 15	86500 (34.1)

28. Secondary Outcome

Title	Population Pharmacokinetics of Carboxydabrafenib - Rm/p
Description	Rm/p is the metabolite-to-parent ratio.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Day 1 (n=1)	3.34 (NA)
Day 15	12.4 (55.8)

29. Secondary Outcome

Title	Population Pharmacokinetics of Carboxydabrafenib - Ctrough
Description	Ctrough is trough concentration.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	5160 (46)

30. Secondary Outcome

Title	Population Pharmacokinetics of Carboxydabrafenib - Racc
Description	Racc is the accumulation ratio.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	1
Geometric Mean (Geometric Coefficient of Variation) [ratio]	1.51 (NA)

31. Secondary Outcome

Title	Population Pharmacokinetics of Trametinib - Cmax
Description	Cmax is the maximum peak concentration.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	9.87 (58.1)
Day 15 (n=18)	25.9 (33.3)

32. Secondary Outcome

Title	Population Pharmacokinetics of Trametinib - Tmax
Description	Tmax is Time to Cmax (maximum peak concentration).
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	1.5
Day 15 (n=18)	11.3

33. Secondary Outcome

Title	Population Pharmacokinetics of Trametinib - AUC(0-t)
Description	Area under the concentration-time curve from time zero (predose) to last time of quantifiable concentration within a subject across all treatments
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	72.6 (27.3)
Day 15 (n=18)	346 (24)

34. Secondary Outcome

Title	Population Pharmacokinetics of Trametinib - AUC(0-24)
Description	AUC is the area under the concentration-time curve.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	20
Day 1	72.7 (27.2)
Day 15 (n=18)	357 (22.7)

35. Secondary Outcome

Title	Population Pharmacokinetics of Trametinib - Ctrough
Description	Ctrough is trough concentration.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	18
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	11.2 (25.2)

36. Secondary Outcome

Title	Population Pharmacokinetics of Trametinib - Racc
Description	Racc is the accumulation ratio.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	15
Geometric Mean (Geometric Coefficient of Variation) [ratio]	5.16 (15.1)

37. Post-Hoc Outcome

Title	All Collected Deaths
Description	Deaths are reported in the following categories: On-treatment deaths are defined as deaths that occurred after treatment start up to 30 days after study drug discontinuation. Post-treatment deaths are defined as deaths that occurred more than 30 days after study drug discontinuation until end of post-treatment follow up. Total deaths are the combination of on-treatment deaths and post-treatment deaths.
Time Frame	The collection period for mortality data occurred from start of treatment until the end of the post-treatment period, up to a maximum timeframe of 4.25 years.

Outcome Measure Data

Analysis Population Description

Safety Set (on-treatment deaths) and Full Analysis Set (total deaths)

Arm/Group Title	Arm 1
Arm/Group Description	All subjects received the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone was to be administered approximately 12 hours after the morning dose. Subjects were to continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Measure Participants	77
Total Deaths	43 55.8%
On-treatment Deaths	16 20.8%
Post-treatment Deaths	27 35.1%

Adverse Events

Time Frame	Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 51 months (for both dabrafenib and also Rametinib) (approx 4.25 years).
Arm/Group Title	All Patients
Arm/Group Description	All Patients
All Cause Mortality
	All Patients
	Affected / at Risk (%)	# Events
Total	16/77 (20.8%)
Serious Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	18/77 (23.4%)
Blood and lymphatic system disorders
Anaemia	1/77 (1.3%)
Eye disorders
Uveitis	1/77 (1.3%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/77 (1.3%)
Pneumoperitoneum	1/77 (1.3%)
General disorders
Pyrexia	1/77 (1.3%)
Hepatobiliary disorders
Acute hepatic failure	1/77 (1.3%)
Liver injury	1/77 (1.3%)
Infections and infestations
Arthritis infective	1/77 (1.3%)
Cellulitis	1/77 (1.3%)
Chikungunya virus infection	1/77 (1.3%)
Diarrhoea infectious	2/77 (2.6%)
Infection	1/77 (1.3%)
Pneumonia	1/77 (1.3%)
Post procedural sepsis	1/77 (1.3%)
Pyelonephritis acute	1/77 (1.3%)
Septic shock	1/77 (1.3%)
Skin infection	1/77 (1.3%)
Soft tissue infection	1/77 (1.3%)
Injury, poisoning and procedural complications
Femur fracture	1/77 (1.3%)
Subdural haematoma	1/77 (1.3%)
Investigations
Ejection fraction decreased	1/77 (1.3%)
White blood cell count decreased	1/77 (1.3%)
Metabolism and nutrition disorders
Hyperglycaemia	1/77 (1.3%)
Hypoglycaemia	1/77 (1.3%)
Psychiatric disorders
Confusional state	1/77 (1.3%)
Reproductive system and breast disorders
Uterine polyp	1/77 (1.3%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	1/77 (1.3%)
Interstitial lung disease	1/77 (1.3%)
Pulmonary embolism	1/77 (1.3%)
Pulmonary haemorrhage	1/77 (1.3%)
Other (Not Including Serious) Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	75/77 (97.4%)
Blood and lymphatic system disorders
Anaemia	37/77 (48.1%)
Gastrointestinal disorders
Abdominal distension	4/77 (5.2%)
Constipation	13/77 (16.9%)
Diarrhoea	10/77 (13%)
Mouth ulceration	4/77 (5.2%)
Nausea	22/77 (28.6%)
Vomiting	18/77 (23.4%)
General disorders
Asthenia	5/77 (6.5%)
Chest discomfort	4/77 (5.2%)
Chest pain	5/77 (6.5%)
Chills	15/77 (19.5%)
Fatigue	7/77 (9.1%)
Malaise	6/77 (7.8%)
Oedema peripheral	6/77 (7.8%)
Pyrexia	46/77 (59.7%)
Infections and infestations
Cystitis	4/77 (5.2%)
Nasopharyngitis	22/77 (28.6%)
Investigations
Alanine aminotransferase increased	19/77 (24.7%)
Aspartate aminotransferase increased	24/77 (31.2%)
Blood alkaline phosphatase increased	20/77 (26%)
Blood lactate dehydrogenase increased	21/77 (27.3%)
Gamma-glutamyltransferase increased	6/77 (7.8%)
Neutrophil count decreased	29/77 (37.7%)
Platelet count decreased	16/77 (20.8%)
Weight decreased	10/77 (13%)
Weight increased	17/77 (22.1%)
White blood cell count decreased	35/77 (45.5%)
Metabolism and nutrition disorders
Decreased appetite	12/77 (15.6%)
Hyperglycaemia	32/77 (41.6%)
Hyperkalaemia	5/77 (6.5%)
Hypoalbuminaemia	5/77 (6.5%)
Hypokalaemia	7/77 (9.1%)
Hyponatraemia	6/77 (7.8%)
Hypoproteinaemia	5/77 (6.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/77 (9.1%)
Back pain	6/77 (7.8%)
Myalgia	11/77 (14.3%)
Pain in extremity	7/77 (9.1%)
Nervous system disorders
Dizziness	19/77 (24.7%)
Headache	13/77 (16.9%)
Psychiatric disorders
Insomnia	6/77 (7.8%)
Respiratory, thoracic and mediastinal disorders
Cough	18/77 (23.4%)
Oropharyngeal pain	4/77 (5.2%)
Skin and subcutaneous tissue disorders
Erythema	4/77 (5.2%)
Panniculitis	5/77 (6.5%)
Pruritus	6/77 (7.8%)
Rash	29/77 (37.7%)
Skin mass	4/77 (5.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.