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Dabrafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Three subjects will receive a single dose of 3 mg/kg dabrafenib on Day 1 and repeat dose will begin from Day 2, evenly divided in two daily doses. Once all 3 subjects have been fully evaluated for the first 28 days (including Day 15 PK) and no DLTs are observed, a next subject will be enrolled at the next higher dose levels (i.e., dose escalation to 3.75 mg/kg \[+1\] and may be further to 4.5 mg/kg \[+2\] and so on). If all 3 subjects have not been fully evaluated for the first 28 days or 1 DLT occurred, the fourth subject will be enrolled at the same dose level. If 2 or more DLTs are observed, the next subject will be enrolled at the next lower dose level (i.e., de-escalated to 2.25 mg/kg \[-1\] and may be further to 1.5 mg/kg \[-2\]). Similarly, the process is repeated for the fifth and sixth subjects in a cohort. All subjects will receive treatment till end of study.

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.

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.

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.

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.

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.

Novartis Pharmaceuticals

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.

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.

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

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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.

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

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.

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 \[GSK2167542\]).

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.

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.

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

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.

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 \[GSK2167542\]).

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.

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.

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 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.

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.

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.

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.

Any sign or symptom that occurs during the treatment period plus 28 days post-treatment.

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.

Part 1 (Dose Escalation): Dabrafenib Treatment (3 mg/kg)

Part 1 (Dose Escalation): Dabrafenib Treatment (3.75 mg/kg)

Part 1 (Dose Escalation): Dabrafenib Treatment (4.5 mg/kg)

Part 1 (Dose Escalation): Dabrafenib Treatment (5.25 mg/kg)

Part 2 (Tumor Specific Expansion): Cohort 1 Low-Grade Gliomas (LGG)

Part 2 (Tumor Specific Expansion): Cohort 2 High-Grade Gliomas (HGG)

Part 2 (Tumor Specific Expansion): Cohort 3 Langerhans Cell Histiocytosis (LCH)

Part 2 (Tumor Specific Expansion): Cohort 4 Miscellaneous Tumors (Other)

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Study Director

All deaths

On-treatment deaths

Adverse Events (AEs)

AEs suspected to be drug related

Serious Adverse Events (SAEs)

SAEs suspected to be drug related

Fatal SAEs

Fatal SAEs suspected to be drug related

AEs leading to discontinuation

AEs requiring dose interruptions

AEs requiring dose reductions

AEs requiring dose reductions or interruptions

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.

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

Week 1 Day 1

Week 3 Day 15

All patients at recommended dose phase 2 (RP2D) of 4,5 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 4,5 mg/kg

All patients at recommended dose phase 2 (RP2D) of 5.25 mg/kg in Part 2 study cohorts (Cohort 1 Low-Grade Gliomas (LGG), Cohort 2 High-Grade Gliomas (HGG), Cohort 3 Langerhans cell histiocytosis (LCH) and Cohort 4 Miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other)) were pooled together.

Part 2 (Tumor Specific Expansion): All Patients at Recommended Dose Phase 2 (RP2D) of 5.25 mg/kg

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

Maximum Concentration (Cmax) of Dabrafenib

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.

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

dabrafenib

hydroxy-dabrafenib

carboxy-dabrafenib

desmethyl-dabrafenib

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

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

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.

The AUC(0-t) of Dabrafenib Metabolites

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.

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

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.

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

hydroxy-dabrafenib @ Week 1 Day 1

hydroxy-dabrafenib @ Week 3 Day 15

carboxy-dabrafenib @ Week 1 Day 1

carboxy-dabrafenib @ Week 3 Day 15

desmethyl-dabrafenib @ Week 1 Day 1

desmethyl-dabrafenib @ Week 3 Day 15

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

Maximum Concentration (Cmax) of Dabrafenib Metabolites

dabrafenib @ Week 1 Day 1

dabrafenib @ Week 3 Day 15

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

Elimination Half Life (T½) of Dabrafenib and Its Metabolites

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

All LGG patients who have been assigned to Recommended Phase II Dose (RP2D) across Part 1 and Part 2.

All LGG Subjects at Recommended Phase 2 Dose (RP2D)

All LGG Subjects

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

All HGG patients who have been assigned to Recommended Phase II Dose (RP2D) across Part 1 and Part 2.

All HGG Subjects at Recommended Phase 2 Dose (RP2D)

All HGG Subjects

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

Participants in the study (all doses and all tumor types) with available pharmacokinetic data

Part 1 and Part 2 - All Participants With PK Data

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.

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

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.

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

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.

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

Post-treatment deaths

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.

Clinical database population; all treated patients.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects	NCT01677741	Neoplasms, Brai...	Dabrafenib	12 Months - 17 Years	Novartis
A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects	NCT01677741	Neoplasms, Brai...	Dabrafenib	12 Months - 17 Years	Novartis

Spots Global Cancer Trial Database for brf116013

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Spots Global Cancer Trial Database for brf116013

Every month we try and update this database with for brf116013 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for brf116013 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.