A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects

Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib in Children and Adolescent Subjects With Advanced BRAF V600-Mutation Positive Solid Tumors

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01677741

Enrollment

Registered

2012-09-03

Start date

2013-05-23

Completion date

2020-12-04

Last updated

2021-11-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neoplasms, Brain

Keywords

Children and Adolescents, BRAF, dabrafenib, dose escalation, BRF116013, V600-mutation positive, BRF

Brief summary

This was a 2-part, Phase I/IIa, multi-center, open label, study in pediatric and adolescent patients with advanced BRAF V600 mutation-positive solid tumors. Part 1 was a dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). Part 2 was an expansion study to further evaluate the safety, tolerability, and clinical activity of dabrafenib in 4 tumor-specific pediatric populations. Patients participated in only either part 1 or part 2 of the study.

Detailed description

Part 1 was a dose escalation study in subjects with any BRAF V600 mutation-positive solid tumor, designed to optimize efficiency of enrollment, minimize the number of subjects being treated at potentially sub-efficacious dose levels, and incorporating the evolving pharmacokinetic, safety and efficacy data from the adult development program. Dose escalation part of the study was to determine the maximum tolerated dose (MTD) and recommend the dose for phase 2 studies (RP2D). An MTD has not been identified for dabrafenib in the adult population. This does not preclude the identification of an MTD in the pediatric population. Modified RSD was employed to determine the MTD. Part 1 used dual criteria of dose limiting toxicity (DLT) and observed dabrafenib exposures to make decisions to advance to the next dose level. Target exposure criteria based on adults treated at the approved adult dose of 300 mg (150 mg given BID) were observed in this study before meeting criteria for stopping dose escalation due to observations of DLTs, and served as the criteria for determining the RP2D for dabrafenib in pediatric subjects. Thus, MTD has not been established in pediatric population, similar to the previous dose finding efforts in adult subjects. Part 2 was a tumor specific expansion study to further evaluate the safety/tolerability profile and to discover possible clinical efficacy of dabrafenib in 4 tumor-specific pediatric populations known to have BRAFV600 activation: high grade glioma (HGG), low grade glioma (LGG), Langerhans cell histiocytosis (LCH), miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other). The exposures for subjects dosed on the basis of weight were also evaluated by age categories.

Interventions

DRUGDabrafenib

Dabrafenib is available as 50 mg or 75 mg capsules and as oral suspension (10 mg/mL for subjects unable to swallow capsules). Dabrafenib (either formulation) will be administered orally as a single dose on Day 1 and twice daily from Day 2, based on weight at the appropriate study dose level.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Months to 17 Years

Healthy volunteers

Inclusion criteria

* Written informed consent - a signed informed consent and/or assent (as age appropriate) will be obtained according to institutional guidelines. * Male or female \>=12 months and \<18 years of age at the time of signing the informed consent form. * Recurrent disease, refractory disease, or progressive disease after having received at least one standard therapy for their disease. Note: Subjects with metastatic (and surgically unresectable) melanoma can be enrolled for first-line treatment; Melanoma subjects with CNS involvement may be enrolled. * At least one evaluable lesion. * BRAF V600 mutation-positive tumor as confirmed in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory or equivalent (the local BRAF testing may be subject to subsequent verification by centralized testing; centralized testing can confirm V600E and V600K mutations only). * Performance score of \>=50% according to the Karnofsky/Lansky performance status scale (subjects with a performance status of \<=50% can be enrolled if the subject's confinement to bed and inability to carry out activities is due solely to cancer-related pain, as assessed by the investigator). * Females of child-bearing potential (with negative serum pregnancy test within 7 days prior to the first dose of study medication) must be willing to practice acceptable methods of birth control . * Sexually active males, who do not agree to abstinence, must be willing to use a condom during intercourse while taking the study drug, and for 16 weeks after stopping treatment and should not father a child in this period. * Must have adequate organ function as defined by the following values: Adequate bone marrow function defined as-absolute neutrophil count (ANC) \>=1000/ microliter (µL), hemoglobin \>=8.0 grams (g)/ deciliter (dL) (may receive red blood cell transfusions), platelets \>=75,000/µL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment). * Adequate renal and metabolic function defined as: calculated glomerular filtration rate (eGFR) (Schwartz formula), or radioisotope GFR \>=90 milliliters/minutes (mL/min)/1.73 meter square (m\^2); or a serum creatinine within the institutional reference range upper limit of normal (for age/gender, if available). * Adequate liver function defined as: bilirubin (sum of conjugated + unconjugated) \<=1.5 x upper limit of normal (ULN) for age, aspartate aminotransaminase (AST) and alanine transaminase (ALT) \<=2.5 x ULN; AST/ALT may be \<5 x ULN at baseline if disease under treatment involves the liver (requires radiographic confirmation of liver involvement). * Adequate cardiac function defined as: left ventricular ejection fraction (LVEF) of either \>=50% by ECHO or greater than institutional lower limit of normal (LLN) by echocardiogram (ECHO) (while not receiving medications for cardiac function), corrected QT using Bazett's (QTcB) interval \<450 milliseconds (msecs).

Exclusion criteria

* Part 2 ONLY: Previous treatment with dabrafenib, another RAF inhibitor, or a mitogen-activated protein kinase (MEK) inhibitor (exception: prior treatment with sorafenib is permitted). * Malignancy OTHER than the BRAF mutant malignancy under study. * Had chemotherapy or radiotherapy within 3 weeks (or 6 weeks for nitrosoureas or mitomycin C) prior to administration of the first dose of study treatment. * The subject has received an investigational product within the following time period prior to the first dosing day in the current study: 28 days or 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is warranted by the data). * History of another malignancy. Exception: (a) Subjects who have been successfully treated and are disease-free for 3 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission are eligible. * Current use of a prohibited medication or herbal preparation or requires any of these medications during the study. * Unresolved toxicity greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 Grade 2 or higher from previous anti-cancer therapy, including major surgery except those that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profile of dabrafenib (e.g., alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based chemotherapy). * Has leukaemia. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib and its excipients. * Autologous or allogeneic stem cell transplant within 3 months prior to enrolment \[NOTE: subjects with evidence of active graph versus host disease are excluded\]. * History of myocardial infarction, severe or unstable angina, peripheral vascular disease or familial QTc prolongation. * Subjects with abnormal cardiac valve morphology (\>=grade 2) documented by echocardiogram (NOTE: subjects with grade 1 abnormalities \[i.e., mild regurgitation/stenosis\] can be entered on study). * Subjects with moderate valvular thickening. * Known, uncontrolled cardiac arrhythmias (except sinus arrhythmia) within the past 24 weeks * Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease or uncontrolled infection), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol. * Presence of active GI disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs. * Hepatitis B Virus, or Hepatitis C Virus infection (subjects with laboratory evidence of Hepatitis B Virus clearance may be enrolled). * Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at screening or prior to dosing. * Lactating females who are actively breast feeding.

Design outcomes

Primary

Measure	Time frame	Description
Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months	The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
Maximum Concentration (Cmax) of Dabrafenib	Week 1 Day 1, Week 3 Day 15	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib was listed and summarized using descriptive statistics.
Area Under the Concentration-time Curve Over the Dosing Interval (AUC(0-τ)) and AUC From Zero to Infinity (AUC(0-inf)) of Dabrafenib	Week 1 Day 1	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUC(0-τ) and AUC(0-inf) of dabrafenib were to be listed and summarized using descriptive statistics.

Secondary

Measure	Time frame	Description
Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Dabrafenib	Week 1 Day 1, Week 3 Day 15	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. CL/F of dabrafenib was to be listed and summarized using descriptive statistics.
Maximum Concentration (Cmax) of Dabrafenib Metabolites	Week 1 Day 1, Week 3 Day 15	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) were listed and summarized using descriptive statistics.
Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	Week 1 Day 1, Week 3 Day 15	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Tmax was listed and summarized using descriptive statistics for dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]).
Elimination Half Life (T½) of Dabrafenib and Its Metabolites	Week 3 Day 15	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. T1/2 of dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) was listed and summarized using descriptive statistics.
Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months	The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Event and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites	Week 3 Day 15	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Pre-dose (trough) concentration (C tau) was to be listed and summarized using descriptive statistics for dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]).
Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects	Up to 6 months	Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR).based on Response Assessment in Neuro-Oncology (RANO) criteria for Low Grade Glioma (LLG) and High Grade Glioma (HGG) subjects.
Effect of Weight on Total Apparent Clearance (CL/F) of Dabrafenib Estimated With a PopPK Model	Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.	The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on total apparent clearance (CL/F) of dabrafenib estimated with the PopPK model is summarized in this record.
Effect of Weight on Volume of Distribution (V/F) of Dabrafenib Estimated With a PopPK Model	Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.	The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on volume of distribution (V/F) of dabrafenib estimated with the PopPK model is summarized in this record.
Effect of Weight on Absorption Rate (ka) of Dabrafenib Estimated With a PopPK Model	Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.	The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on absorption rate (ka) of dabrafenib estimated with a PopPK model is summarized in this record.
Effect of Weight on Coefficients for Significant Covariates of Dabrafenib Estimated With a PopPK Model	Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.	The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on coefficients for significant covariates of dabrafenib estimated with a PopPK model is summarized in this record.
Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects	Up to 6 months	Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR).based on Response Assessment in Neuro-Oncology (RANO) criteria for Low Grade Glioma (LLG) and High Grade Glioma (HGG) subjects.
The AUC(0-t) of Dabrafenib Metabolites	Week 1 Day 1, Week 3 Day 15	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC\[0-t\]) dabrafenib metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) were to be listed and summarized using descriptive statistics.
The AUC(0-tau) of Dabrafenib and Its Metabolites	Week 1 Day 1, Week 3 Day 15	Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-tau) of dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) were to be listed and summarized using descriptive statistics.

Countries

Australia, Canada, Denmark, France, Germany, Israel, Italy, Spain, United Kingdom, United States

Participant flow

Recruitment details

This study was conducted in 19 centers in eight participating countries: Australia (1), Canada (1), Denmark (1), Germany (1), France (4), Spain (1), United Kingdom (2), and United States (8).

Pre-assignment details

Patients participated in only either Part 1 (Dose Escalation) or Part 2 (Tumor specific expansion) of the study.

Participants by arm

Arm	Count
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg) Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.	3
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg) Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.	10
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg) Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.	8
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg) Repeat dose, dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). The RSD was built on the classic 3+3 design, but allowed for continued recruitment of subjects while the data from the first 3 subjects in each cohort was collected (up to 6 subjects per cohort). The starting dose was 3 mg/kg with subsequent dose levels: 3.75 mg/kg, 4.5 mg/kg, 5.25 mg/kg and 6.0 mg/kg.	6
Part 2 (Tumor Specific Expansion): Cohort 1 Low-Grade Gliomas (LGG) Subjects with low-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.	17
Part 2 (Tumor Specific Expansion): Cohort 2 High-Grade Gliomas (HGG) Subjects with high-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.	28
Part 2 (Tumor Specific Expansion): Cohort 3 Langerhans Cell Histiocytosis (LCH) Subjects with LCH with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.	11
Part 2 (Tumor Specific Expansion): Cohort 4 Miscellaneous Tumors (Other) Subjects with other tumors with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.	2
Total	85

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007
Overall Study	Death	0	0	0	1	0	1	0	0
Overall Study	Enrolled in a rollover study	0	3	2	1	6	6	7	0
Overall Study	Progressive disease	1	0	1	0	0	1	0	0
Overall Study	Withdrawal by Subject	2	7	5	4	11	20	4	2

Baseline characteristics

Characteristic	Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Total	Part 2 (Tumor Specific Expansion): Cohort 4 Miscellaneous Tumors (Other)	Part 2 (Tumor Specific Expansion): Cohort 3 Langerhans Cell Histiocytosis (LCH)	Part 2 (Tumor Specific Expansion): Cohort 2 High-Grade Gliomas (HGG)	Part 2 (Tumor Specific Expansion): Cohort 1 Low-Grade Gliomas (LGG)	Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)
Age, Continuous	9.33 Years STANDARD_DEVIATION 5.132	9.46 Years STANDARD_DEVIATION 5.051	9.50 Years STANDARD_DEVIATION 10.607	5.52 Years STANDARD_DEVIATION 3.39	12.32 Years STANDARD_DEVIATION 3.692	9.65 Years STANDARD_DEVIATION 5.195	7.17 Years STANDARD_DEVIATION 3.189	6.58 Years STANDARD_DEVIATION 5.445	11.30 Years STANDARD_DEVIATION 5.355
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	7 Participants	0 Participants	0 Participants	3 Participants	2 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) Black or African American	0 Participants	4 Participants	0 Participants	0 Participants	1 Participants	2 Participants	0 Participants	1 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	72 Participants	2 Participants	11 Participants	22 Participants	13 Participants	6 Participants	7 Participants	8 Participants
Sex: Female, Male Female	1 Participants	35 Participants	0 Participants	4 Participants	11 Participants	8 Participants	3 Participants	3 Participants	5 Participants
Sex: Female, Male Male	2 Participants	50 Participants	2 Participants	7 Participants	17 Participants	9 Participants	3 Participants	5 Participants	5 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk
deaths Total, all-cause mortality	0 / 3	0 / 10	0 / 8	1 / 6	0 / 17	0 / 28	0 / 11	0 / 2
other Total, other adverse events	3 / 3	10 / 10	8 / 8	6 / 6	17 / 17	26 / 28	11 / 11	2 / 2
serious Total, serious adverse events	0 / 3	5 / 10	5 / 8	3 / 6	7 / 17	13 / 28	6 / 11	0 / 2

Outcome results

Primary

Area Under the Concentration-time Curve Over the Dosing Interval (AUC(0-τ)) and AUC From Zero to Infinity (AUC(0-inf)) of Dabrafenib

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUC(0-τ) and AUC(0-inf) of dabrafenib were to be listed and summarized using descriptive statistics.

Time frame: Week 1 Day 1

Population: Pharmacokinetic population. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable AUC(0-t) and AUC (0-inf) PK parameters were collected/calculated.

Primary

Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)

The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.

Time frame: From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months

Population: Safety population. Deaths occurring more than 28 days after the last dose of study drug were not included in the on-treatment deaths. All deaths included on-treatment deaths and those occurring more than 28 days after the last dose of study drug.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose interruptions	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose reductions or interruptions	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Fatal SAEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	All deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs leading to discontinuation	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Adverse Events (AEs)	3 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs suspected to be drug related	3 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	On-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose reductions	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Serious Adverse Events (SAEs)	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	SAEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Fatal SAEs	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	On-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Fatal SAEs	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs suspected to be drug related	10 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs leading to discontinuation	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose interruptions	5 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Fatal SAEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	All deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	SAEs suspected to be drug related	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Serious Adverse Events (SAEs)	5 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Adverse Events (AEs)	10 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose reductions or interruptions	5 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose reductions	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Fatal SAEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	All deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	On-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Adverse Events (AEs)	8 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs suspected to be drug related	8 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Serious Adverse Events (SAEs)	5 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	SAEs suspected to be drug related	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Fatal SAEs	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs leading to discontinuation	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose interruptions	6 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose reductions	3 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose reductions or interruptions	6 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	SAEs suspected to be drug related	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Serious Adverse Events (SAEs)	3 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	All deaths	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose interruptions	5 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs suspected to be drug related	5 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Adverse Events (AEs)	6 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose reductions or interruptions	5 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs requiring dose reductions	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Fatal SAEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	Fatal SAEs	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	On-treatment deaths	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)	AEs leading to discontinuation	0 Participants

Primary

Maximum Concentration (Cmax) of Dabrafenib

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib was listed and summarized using descriptive statistics.

Time frame: Week 1 Day 1, Week 3 Day 15

Population: Pharmacokinetic population. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib	Week 1 Day 1	1820 ng/mL	Geometric Coefficient of Variation 38
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib	Week 3 Day 15	1470 ng/mL	Geometric Coefficient of Variation 37.7
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib	Week 1 Day 1	1250 ng/mL	Geometric Coefficient of Variation 61.5
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib	Week 3 Day 15	1260 ng/mL	Geometric Coefficient of Variation 48.1
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib	Week 1 Day 1	1250 ng/mL	Geometric Coefficient of Variation 529.9
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib	Week 3 Day 15	1580 ng/mL	Geometric Coefficient of Variation 49.2
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib	Week 1 Day 1	1900 ng/mL	Geometric Coefficient of Variation 45
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib	Week 3 Day 15	1710 ng/mL	Geometric Coefficient of Variation 56.4
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Maximum Concentration (Cmax) of Dabrafenib	Week 1 Day 1	1340 ng/mL	Geometric Coefficient of Variation 82.6
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Maximum Concentration (Cmax) of Dabrafenib	Week 3 Day 15	1450 ng/mL	Geometric Coefficient of Variation 57.8
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Maximum Concentration (Cmax) of Dabrafenib	Week 1 Day 1	1550 ng/mL	Geometric Coefficient of Variation 56.8
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Maximum Concentration (Cmax) of Dabrafenib	Week 3 Day 15	1310 ng/mL	Geometric Coefficient of Variation 49.4

Secondary

Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Dabrafenib

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. CL/F of dabrafenib was to be listed and summarized using descriptive statistics.

Time frame: Week 1 Day 1, Week 3 Day 15

Population: Pharmacokinetic population. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable CL/F PK parameters were collected/calculated.

Secondary

Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects

Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR).based on Response Assessment in Neuro-Oncology (RANO) criteria for Low Grade Glioma (LLG) and High Grade Glioma (HGG) subjects.

Time frame: Up to 6 months

Population: All treated population

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects	7 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects	7 Participants
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects	10 Participants

Secondary

Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects

Time frame: Up to 6 months

Population: All treated population

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects	3 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects	5 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects	4 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects	12 Participants
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects	17 Participants
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects	24 Participants

Secondary

Effect of Weight on Absorption Rate (ka) of Dabrafenib Estimated With a PopPK Model

The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on absorption rate (ka) of dabrafenib estimated with a PopPK model is summarized in this record.

Time frame: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Population: All subjects who received at least one dose of dabrafenib in Part 1 and 2 and provided an evaluable PK profile. The covariate weight did not meet the pre-specified criteria to be considered a significant covariate on Ka based on the goodness-of-fit plots and the decrease of the objective function provided by the PopPK software (NONMEM). Therefore, effect of weight on Ka could not be calculated.

Arm	Measure	Value (NUMBER)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Effect of Weight on Absorption Rate (ka) of Dabrafenib Estimated With a PopPK Model	NA coefficient

Secondary

Effect of Weight on Coefficients for Significant Covariates of Dabrafenib Estimated With a PopPK Model

The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on coefficients for significant covariates of dabrafenib estimated with a PopPK model is summarized in this record.

Time frame: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Population: All subjects who received at least one dose of dabrafenib in Part 1 and 2 and provided an evaluable PK profile. The covariate weight did not meet the pre-specified criteria to be considered a significant covariate based on the goodness-of-fit plots and the decrease of the objective function provided by the PopPK software (NONMEM). Therefore, effect of weight on coefficients for significant covariates of dabrafenib could not be calculated.

Arm	Measure	Value (NUMBER)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Effect of Weight on Coefficients for Significant Covariates of Dabrafenib Estimated With a PopPK Model	NA coefficient

Secondary

Effect of Weight on Total Apparent Clearance (CL/F) of Dabrafenib Estimated With a PopPK Model

The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on total apparent clearance (CL/F) of dabrafenib estimated with the PopPK model is summarized in this record.

Time frame: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Population: All subjects who received at least one dose of dabrafenib in Part 1 and 2 and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.

Arm	Measure	Value (NUMBER)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Effect of Weight on Total Apparent Clearance (CL/F) of Dabrafenib Estimated With a PopPK Model	0.223 coefficient

Secondary

Effect of Weight on Volume of Distribution (V/F) of Dabrafenib Estimated With a PopPK Model

The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of weight on volume of distribution (V/F) of dabrafenib estimated with the PopPK model is summarized in this record.

Time frame: Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.

Arm	Measure	Value (NUMBER)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Effect of Weight on Volume of Distribution (V/F) of Dabrafenib Estimated With a PopPK Model	0.593 coefficient

Secondary

Elimination Half Life (T½) of Dabrafenib and Its Metabolites

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. T1/2 of dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) was listed and summarized using descriptive statistics.

Time frame: Week 3 Day 15

Population: Pharmacokinetic population. For each parameter, only participants with an evaluable PK sample collected were included in the analysis.

Arm	Measure	Group	Value (MEAN)	Dispersion
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Elimination Half Life (T½) of Dabrafenib and Its Metabolites	dabrafenib	1.98 Hour (hr)	Standard Deviation 0.687
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Elimination Half Life (T½) of Dabrafenib and Its Metabolites	dabrafenib	2.85 Hour (hr)	Standard Deviation 1.58
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Elimination Half Life (T½) of Dabrafenib and Its Metabolites	dabrafenib	2.74 Hour (hr)	Standard Deviation 0.84
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Elimination Half Life (T½) of Dabrafenib and Its Metabolites	dabrafenib	1.56 Hour (hr)	Standard Deviation 0.359
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Elimination Half Life (T½) of Dabrafenib and Its Metabolites	dabrafenib	3.03 Hour (hr)	Standard Deviation 2.27
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Elimination Half Life (T½) of Dabrafenib and Its Metabolites	dabrafenib	2.54 Hour (hr)	Standard Deviation 2.44

Secondary

Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)

The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Event and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

Time frame: From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose interruptions	10 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose reductions or interruptions	10 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Fatal SAEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	All deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs leading to discontinuation	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Adverse Events (AEs)	17 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs suspected to be drug related	16 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	On-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose reductions	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Serious Adverse Events (SAEs)	7 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	SAEs suspected to be drug related	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Fatal SAEs	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	On-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Fatal SAEs	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs suspected to be drug related	26 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs leading to discontinuation	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose interruptions	13 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Fatal SAEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	All deaths	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	SAEs suspected to be drug related	3 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Serious Adverse Events (SAEs)	13 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Adverse Events (AEs)	26 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose reductions or interruptions	13 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose reductions	4 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Fatal SAEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	All deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	On-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Adverse Events (AEs)	11 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs suspected to be drug related	11 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Serious Adverse Events (SAEs)	6 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	SAEs suspected to be drug related	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Fatal SAEs	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs leading to discontinuation	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose interruptions	7 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose reductions	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose reductions or interruptions	7 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	SAEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Serious Adverse Events (SAEs)	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	All deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose interruptions	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Adverse Events (AEs)	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose reductions or interruptions	2 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs requiring dose reductions	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Fatal SAEs suspected to be drug related	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	Fatal SAEs	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	On-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)	AEs leading to discontinuation	0 Participants

Secondary

Maximum Concentration (Cmax) of Dabrafenib Metabolites

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) were listed and summarized using descriptive statistics.

Time frame: Week 1 Day 1, Week 3 Day 15

Population: Pharmacokinetic population. For each parameter, only participants with an evaluable PK sample collected at each timepoint were included in the analysis.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	811 ng/mL	Geometric Coefficient of Variation 24.7
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	673 ng/mL	Geometric Coefficient of Variation 62.8
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 1 Day 1	1720 ng/mL	Geometric Coefficient of Variation 90.6
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 3 Day 15	4700 ng/mL	Geometric Coefficient of Variation 51.7
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	13.0 ng/mL	Geometric Coefficient of Variation 27.3
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	194 ng/mL	Geometric Coefficient of Variation 219.4
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	726 ng/mL	Geometric Coefficient of Variation 37.6
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 3 Day 15	6410 ng/mL	Geometric Coefficient of Variation 28
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	311 ng/mL	Geometric Coefficient of Variation 78.9
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	662 ng/mL	Geometric Coefficient of Variation 66.7
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 1 Day 1	1300 ng/mL	Geometric Coefficient of Variation 55.7
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	6.55 ng/mL	Geometric Coefficient of Variation 80.5
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	317 ng/mL	Geometric Coefficient of Variation 324.9
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	15.4 ng/mL	Geometric Coefficient of Variation 103.9
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 3 Day 15	9650 ng/mL	Geometric Coefficient of Variation 35.9
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 1 Day 1	824 ng/mL	Geometric Coefficient of Variation 291.3
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	473 ng/mL	Geometric Coefficient of Variation 1643.7
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	752 ng/mL	Geometric Coefficient of Variation 32.8
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 3 Day 15	11200 ng/mL	Geometric Coefficient of Variation 28.4
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	1010 ng/mL	Geometric Coefficient of Variation 51.5
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 1 Day 1	4250 ng/mL	Geometric Coefficient of Variation 67
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	238 ng/mL	Geometric Coefficient of Variation 45.6
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	23.7 ng/mL	Geometric Coefficient of Variation 53.8
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	1370 ng/mL	Geometric Coefficient of Variation 43.9
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	694 ng/mL	Geometric Coefficient of Variation 77.9
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	10.7 ng/mL	Geometric Coefficient of Variation 159.4
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	772 ng/mL	Geometric Coefficient of Variation 50.1
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 1 Day 1	1650 ng/mL	Geometric Coefficient of Variation 161.2
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 3 Day 15	8280 ng/mL	Geometric Coefficient of Variation 45.9
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	328 ng/mL	Geometric Coefficient of Variation 38.8
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 3 Day 15	7970 ng/mL	Geometric Coefficient of Variation 30
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	carboxy-dabrafenib @ Week 1 Day 1	2330 ng/mL	Geometric Coefficient of Variation 97.6
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	10.1 ng/mL	Geometric Coefficient of Variation 88.7
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	274 ng/mL	Geometric Coefficient of Variation 77.4
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	711 ng/mL	Geometric Coefficient of Variation 43.4
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Maximum Concentration (Cmax) of Dabrafenib Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	894 ng/mL	Geometric Coefficient of Variation 58.2

Secondary

Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Pre-dose (trough) concentration (C tau) was to be listed and summarized using descriptive statistics for dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]).

Time frame: Week 3 Day 15

Population: Pharmacokinetic population. For each parameter, only participants with an evaluable PK sample collected were included in the analysis.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites	dabrafenib	11.9 ng/mL	Geometric Coefficient of Variation 276.5
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites	dabrafenib	39.8 ng/mL	Geometric Coefficient of Variation 176.1
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites	dabrafenib	50.7 ng/mL	Geometric Coefficient of Variation 121
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites	dabrafenib	11.0 ng/mL	Geometric Coefficient of Variation 67.5
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites	dabrafenib	42.7 ng/mL	Geometric Coefficient of Variation 135.9
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites	dabrafenib	22.8 ng/mL	Geometric Coefficient of Variation 209.5

Secondary

The AUC(0-tau) of Dabrafenib and Its Metabolites

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-tau) of dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) were to be listed and summarized using descriptive statistics.

Time frame: Week 1 Day 1, Week 3 Day 15

Population: Pharmacokinetic population. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable AUC(0-tau) PK parameters were collected/calculated.

Secondary

The AUC(0-t) of Dabrafenib Metabolites

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC\[0-t\]) dabrafenib metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]) were to be listed and summarized using descriptive statistics.

Time frame: Week 1 Day 1, Week 3 Day 15

Population: Pharmacokinetic population. Due to limited dabrafenib PK data collected for Day 1 (up to 4 hours post-dose PK data only), no reliable AUC(0-t) PK parameters were collected/calculated.

Secondary

Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites

Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Tmax was listed and summarized using descriptive statistics for dabrafenib and its metabolites (hydroxy-dabrafenib \[GSK2285403\], carboxy-dabrafenib \[GSK2298683\], and desmethyl-dabrafenib \[GSK2167542\]).

Time frame: Week 1 Day 1, Week 3 Day 15

Population: Pharmacokinetic population. For each parameter, only participants with an evaluable PK sample collected at each timepoint were included in the analysis.

Arm	Measure	Group	Value (MEDIAN)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 3 Day 15	1.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 1 Day 1	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 3 Day 15	6.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	2.50 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 1 Day 1	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 3 Day 15	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	3.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	1.50 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 3 Day 15	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 1 Day 1	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 3 Day 15	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 1 Day 1	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	3.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	1.50 Hour (hr)
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 1 Day 1	2.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 3 Day 15	4.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 3 Day 15	1.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	hydroxy-dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	carboxy-dabrafenib @ Week 3 Day 15	4.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 3 Day 15	2.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	desmethyl-dabrafenib @ Week 1 Day 1	4.00 Hour (hr)
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites	dabrafenib @ Week 1 Day 1	2.00 Hour (hr)

Post Hoc

All Collected Deaths in Parts I and II

On treatment deaths were collected from FPFT up to 28 days after study drug discontinuation, for a maximum duration of 360 weeks in Part I (treatment duration ranged from 5.6 to 356.0 weeks) and a maximum duration of 300 weeks in Part II (treatment duration ranged from 0.3 to 296.0 weeks). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 7 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.

Time frame: up to 360 weeks (on-treatment in Part I), up to 300 weeks (on-treatment in Part II), up to approximately 7 years (study duration)

Population: Clinical database population; all treated patients.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	All Collected Deaths in Parts I and II	On-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	All Collected Deaths in Parts I and II	All deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)	All Collected Deaths in Parts I and II	Post-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	All Collected Deaths in Parts I and II	All deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	All Collected Deaths in Parts I and II	Post-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)	All Collected Deaths in Parts I and II	On-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	All Collected Deaths in Parts I and II	All deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	All Collected Deaths in Parts I and II	On-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)	All Collected Deaths in Parts I and II	Post-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	All Collected Deaths in Parts I and II	On-treatment deaths	1 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	All Collected Deaths in Parts I and II	Post-treatment deaths	0 Participants
Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)	All Collected Deaths in Parts I and II	All deaths	1 Participants
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	All Collected Deaths in Parts I and II	Post-treatment deaths	0 Participants
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	All Collected Deaths in Parts I and II	On-treatment deaths	0 Participants
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg	All Collected Deaths in Parts I and II	All deaths	0 Participants
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	All Collected Deaths in Parts I and II	Post-treatment deaths	1 Participants
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	All Collected Deaths in Parts I and II	On-treatment deaths	0 Participants
Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg	All Collected Deaths in Parts I and II	All deaths	1 Participants
Part 2 (Tumor Specific Expansion): Cohort 3 Langerhans Cell Histiocytosis (LCH)	All Collected Deaths in Parts I and II	Post-treatment deaths	0 Participants
Part 2 (Tumor Specific Expansion): Cohort 3 Langerhans Cell Histiocytosis (LCH)	All Collected Deaths in Parts I and II	On-treatment deaths	0 Participants
Part 2 (Tumor Specific Expansion): Cohort 3 Langerhans Cell Histiocytosis (LCH)	All Collected Deaths in Parts I and II	All deaths	0 Participants
Part 2 (Tumor Specific Expansion): Cohort 4 Miscellaneous Tumors (Other)	All Collected Deaths in Parts I and II	On-treatment deaths	0 Participants
Part 2 (Tumor Specific Expansion): Cohort 4 Miscellaneous Tumors (Other)	All Collected Deaths in Parts I and II	Post-treatment deaths	0 Participants
Part 2 (Tumor Specific Expansion): Cohort 4 Miscellaneous Tumors (Other)	All Collected Deaths in Parts I and II	All deaths	0 Participants

Source: ClinicalTrials.gov · Data processed: May 29, 2026

A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Area Under the Concentration-time Curve Over the Dosing Interval (AUC(0-τ)) and AUC From Zero to Infinity (AUC(0-inf)) of Dabrafenib

Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)

Maximum Concentration (Cmax) of Dabrafenib

Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Dabrafenib

Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects

Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects

Effect of Weight on Absorption Rate (ka) of Dabrafenib Estimated With a PopPK Model

Effect of Weight on Coefficients for Significant Covariates of Dabrafenib Estimated With a PopPK Model

Effect of Weight on Total Apparent Clearance (CL/F) of Dabrafenib Estimated With a PopPK Model

Effect of Weight on Volume of Distribution (V/F) of Dabrafenib Estimated With a PopPK Model

Elimination Half Life (T½) of Dabrafenib and Its Metabolites

Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)

Maximum Concentration (Cmax) of Dabrafenib Metabolites

Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites

The AUC(0-tau) of Dabrafenib and Its Metabolites

The AUC(0-t) of Dabrafenib Metabolites

Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites

All Collected Deaths in Parts I and II