Study to Investigate the Objective Response Rate of Dabra... | NCT02083354

NCT02083354

ID	Type	Description	Link
CDRB436B2205	Other Identifier	Novartis

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Arm 1	Experimental	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 Drug: Trametinib

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Dabrafenib	Drug	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)	Arm 1

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Objective Response Rate (ORR)	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.	Up to 35 months

Secondary Outcomes

Measure	Description	Time Frame
Progression-free Survival (PFS) - Median	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	Up to 36 months
Progression-free Survival (PFS)

Eligibility Module

Eligibility Criteria

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/Locations Module

Name	Affiliation	Role
Novartis Pharmaceuticals	Novartis Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Novartis Investigative Site		Guangzhou	Guangdong	510060	China
Novartis Investigative Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
34504796	Derived	Mao L, Ding Y, Bai X, Sheng X, Dai J, Chi Z, Cui C, Kong Y, Fan Y, Xu Y, Wang X, Tang B, Lian B, Yan X, Li S, Zhou L, Wei X, Li C, Guo J, Zhang X, Si L. Overall Survival of Patients With Unresectable or Metastatic BRAF V600-Mutant Acral/Cutaneous Melanoma Administered Dabrafenib Plus Trametinib: Long-Term Follow-Up of a Multicenter, Single-Arm Phase IIa Trial. Front Oncol. 2021 Aug 24;11:720044. doi: 10.3389/fonc.2021.720044. eCollection 2021.
32534242

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Arm 1	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

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Nov 27, 2019	Feb 15, 2021

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

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.

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	Arm 1	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

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00050.6± 13.08

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00042
Male	BG00035

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000
Asian	BG00077

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Objective Response Rate (ORR)

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.

Full Analysis Set

Posted

Number

95% Confidence Interval

Percentage of Participants

Up to 35 months

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG00077

Title

Denominators

Categories

Title	Measurements
	OG00061(49.2 to 72.0)

Secondary

Progression-free Survival (PFS) - Median

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

Full analysis set

Posted

Median

95% Confidence Interval

months

Up to 36 months

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Progression-free Survival (PFS)

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.

Full analysis set

Posted

Count of Participants

Participants

Up to 36 months

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Duration of Response (DOR) - Estimate for Duration of Response - Median

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.

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

Posted

Median

95% Confidence Interval

Months

Up to 36 months

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Duration of Response (DOR)

Full analysis set

Posted

Count of Participants

Participants

Up to 36 months

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Overall Survival (OS) - Median

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

Full analysis set

Posted

Median

95% Confidence Interval

Months

Approximately 5 years

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Overall Survival (OS)

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.

Full analysis set

Posted

Count of Participants

Participants

Approximately 5 years

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Number of Participants With Adverse Events

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.

Safety set

Posted

Count of Participants

Participants

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).

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants

Secondary

Population Pharmacokinetics of Dabrafenib - Cmax

Cmax is the maximum peak concentration.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Dabrafenib - Tmax

Tmax is Time to Cmax (maximum peak concentration).

PK analysis set

Posted

Median

Full Range

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Dabrafenib - AUC(0-12)

AUC is the area under the concentration-time curve.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

h.ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Dabrafenib - Ctrough

Ctrough is trough concentration.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Dabrafenib - Racc

Racc is the accumulation ratio.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Hydroxydabrafenib - Cmax

Cmax is the maximum peak concentration.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Hydroxydabrafenib - Tmax

Tmax is Time to Cmax (maximum peak concentration).

PK analysis set

Posted

Median

Full Range

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Hydroxydabrafenib - AUC(0-12)

AUC is the area under the concentration-time curve.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

h.ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Hydroxydabrafenib - Rm/p

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

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Hydroxydabrafenib - Ctrough

Ctrough is trough concentration.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Hydroxydabrafenib - Racc

Racc is the accumulation ratio.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Desmethyl-dabrafenib - Cmax

Cmax is the maximum peak concentration.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Desmethyl-dabrafenib - Tmax

Tmax is Time to Cmax (maximum peak concentration).

PK analysis set

Posted

Median

Full Range

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Desmethyl-dabrafenib - AUC(0-12)

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.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

h.ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Desmethyl-dabrafenib - Rm/p

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.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Desmethyl-dabrafenib - Ctrough

Ctrough is trough concentration.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Carboxydabrafenib - Cmax

Cmax is the maximum peak concentration.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Carboxydabrafenib - Tmax

Tmax is Time to Cmax (maximum peak concentration).

PK analysis set

Posted

Median

Full Range

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Carboxydabrafenib - AUC(0-12)

AUC is the area under the concentration-time curve.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

h.ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Carboxydabrafenib - Rm/p

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

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Carboxydabrafenib - Ctrough

Ctrough is trough concentration.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Carboxydabrafenib - Racc

Racc is the accumulation ratio.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Trametinib - Cmax

Cmax is the maximum peak concentration.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Trametinib - Tmax

Tmax is Time to Cmax (maximum peak concentration).

PK analysis set

Posted

Median

Full Range

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Trametinib - AUC(0-t)

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

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

h.ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Trametinib - AUC(0-24)

AUC is the area under the concentration-time curve.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

h.ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Trametinib - Ctrough

Ctrough is trough concentration.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Secondary

Population Pharmacokinetics of Trametinib - Racc

Racc is the accumulation ratio.

PK analysis set

Posted

Geometric Mean

Geometric Coefficient of Variation

ratio

Day 1 and Day 15

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Post-Hoc

All Collected Deaths

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.

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

Posted

Number

Participants

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.

ID	Title	Description
OG000	Arm 1	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

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Uveitis	Eye disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Pneumoperitoneum	Gastrointestinal disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Pyrexia	General disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Acute hepatic failure	Hepatobiliary disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Liver injury	Hepatobiliary disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Arthritis infective	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Cellulitis	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Chikungunya virus infection	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Diarrhoea infectious	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0002 affected77 at risk
Infection	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Pneumonia	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Post procedural sepsis	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Pyelonephritis acute	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Septic shock	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Skin infection	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Soft tissue infection	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Subdural haematoma	Injury, poisoning and procedural complications	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Ejection fraction decreased	Investigations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
White blood cell count decreased	Investigations	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Confusional state	Psychiatric disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Uterine polyp	Reproductive system and breast disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Interstitial lung disease	Respiratory, thoracic and mediastinal disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk
Pulmonary haemorrhage	Respiratory, thoracic and mediastinal disorders	MedDRA (24.0)	Systematic Assessment	EG0001 affected77 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (24.0)	Systematic Assessment	EG00037 affected77 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA (24.0)	Systematic Assessment	EG0004 affected77 at risk
Constipation	Gastrointestinal disorders	MedDRA (24.0)	Systematic Assessment	EG00013 affected77 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (24.0)	Systematic Assessment	EG00010 affected77 at risk
Mouth ulceration	Gastrointestinal disorders	MedDRA (24.0)	Systematic Assessment	EG0004 affected77 at risk
Nausea	Gastrointestinal disorders	MedDRA (24.0)	Systematic Assessment	EG00022 affected77 at risk
Vomiting	Gastrointestinal disorders	MedDRA (24.0)	Systematic Assessment	EG00018 affected77 at risk
Asthenia	General disorders	MedDRA (24.0)	Systematic Assessment	EG0005 affected77 at risk
Chest discomfort	General disorders	MedDRA (24.0)	Systematic Assessment	EG0004 affected77 at risk
Chest pain	General disorders	MedDRA (24.0)	Systematic Assessment	EG0005 affected77 at risk
Chills	General disorders	MedDRA (24.0)	Systematic Assessment	EG00015 affected77 at risk
Fatigue	General disorders	MedDRA (24.0)	Systematic Assessment	EG0007 affected77 at risk
Malaise	General disorders	MedDRA (24.0)	Systematic Assessment	EG0006 affected77 at risk
Oedema peripheral	General disorders	MedDRA (24.0)	Systematic Assessment	EG0006 affected77 at risk
Pyrexia	General disorders	MedDRA (24.0)	Systematic Assessment	EG00046 affected77 at risk
Cystitis	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG0004 affected77 at risk
Nasopharyngitis	Infections and infestations	MedDRA (24.0)	Systematic Assessment	EG00022 affected77 at risk
Alanine aminotransferase increased	Investigations	MedDRA (24.0)	Systematic Assessment	EG00019 affected77 at risk
Aspartate aminotransferase increased	Investigations	MedDRA (24.0)	Systematic Assessment	EG00024 affected77 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA (24.0)	Systematic Assessment	EG00020 affected77 at risk
Blood lactate dehydrogenase increased	Investigations	MedDRA (24.0)	Systematic Assessment	EG00021 affected77 at risk
Gamma-glutamyltransferase increased	Investigations	MedDRA (24.0)	Systematic Assessment	EG0006 affected77 at risk
Neutrophil count decreased	Investigations	MedDRA (24.0)	Systematic Assessment	EG00029 affected77 at risk
Platelet count decreased	Investigations	MedDRA (24.0)	Systematic Assessment	EG00016 affected77 at risk
Weight decreased	Investigations	MedDRA (24.0)	Systematic Assessment	EG00010 affected77 at risk
Weight increased	Investigations	MedDRA (24.0)	Systematic Assessment	EG00017 affected77 at risk
White blood cell count decreased	Investigations	MedDRA (24.0)	Systematic Assessment	EG00035 affected77 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA (24.0)	Systematic Assessment	EG00012 affected77 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (24.0)	Systematic Assessment	EG00032 affected77 at risk
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA (24.0)	Systematic Assessment	EG0005 affected77 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA (24.0)	Systematic Assessment	EG0005 affected77 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (24.0)	Systematic Assessment	EG0007 affected77 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA (24.0)	Systematic Assessment	EG0006 affected77 at risk
Hypoproteinaemia	Metabolism and nutrition disorders	MedDRA (24.0)	Systematic Assessment	EG0005 affected77 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (24.0)	Systematic Assessment	EG0007 affected77 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (24.0)	Systematic Assessment	EG0006 affected77 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA (24.0)	Systematic Assessment	EG00011 affected77 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (24.0)	Systematic Assessment	EG0007 affected77 at risk
Dizziness	Nervous system disorders	MedDRA (24.0)	Systematic Assessment	EG00019 affected77 at risk
Headache	Nervous system disorders	MedDRA (24.0)	Systematic Assessment	EG00013 affected77 at risk
Insomnia	Psychiatric disorders	MedDRA (24.0)	Systematic Assessment	EG0006 affected77 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (24.0)	Systematic Assessment	EG00018 affected77 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA (24.0)	Systematic Assessment	EG0004 affected77 at risk
Erythema	Skin and subcutaneous tissue disorders	MedDRA (24.0)	Systematic Assessment	EG0004 affected77 at risk
Panniculitis	Skin and subcutaneous tissue disorders	MedDRA (24.0)	Systematic Assessment	EG0005 affected77 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA (24.0)	Systematic Assessment	EG0006 affected77 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA (24.0)	Systematic Assessment	EG00029 affected77 at risk
Skin mass	Skin and subcutaneous tissue disorders	MedDRA (24.0)	Systematic Assessment	EG0004 affected77 at risk

ID	Term
D009369	Neoplasms
D008545	Melanoma
D012878	Skin Neoplasms

Ancestor Terms

ID	Term
D018358	Neuroendocrine Tumors
D017599	Neuroectodermal Tumors
D009373	Neoplasms, Germ Cell and Embryonal
D009370	Neoplasms by Histologic Type
D009380	Neoplasms, Nerve Tissue
D018326	Nevi and Melanomas
D009371	Neoplasms by Site
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases

ID	Term
C561627	dabrafenib
C560077	trametinib