A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
ClinicalTrials.gov Identifier: NCT01677741 |
Recruitment Status :
Completed
First Posted : September 3, 2012
Last Update Posted : March 4, 2021
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Condition or disease | Intervention/treatment | Phase |
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Neoplasms, Brain | Drug: Dabrafenib | Phase 1 Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 86 participants |
Allocation: | Non-Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | 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 |
Actual Study Start Date : | February 27, 2013 |
Actual Primary Completion Date : | December 4, 2020 |
Actual Study Completion Date : | December 4, 2020 |

Arm | Intervention/treatment |
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Experimental: Part 1: Dabrafenib treatment
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.
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Drug: Dabrafenib
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. |
Experimental: Part 2: Cohort 1 Low-Grade Gliomas with BRAF V600 mutations
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.
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Drug: Dabrafenib
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. |
Experimental: Part 2: Cohort 2 High-Grade Gliomas with BRAF V600 mutations
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.
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Drug: Dabrafenib
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. |
Experimental: Part 2: Cohort 3 LCH with BRAF V600 mutations
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.
|
Drug: Dabrafenib
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. |
Experimental: Part 2: Cohort 4 Melanoma and PTC with BRAF V600 mutations
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.
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Drug: Dabrafenib
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. |
- Incidence of traetment emergent Adverse Events (AEs) [ Time Frame: Up to 6 months ]The distribution of adverse events will be 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.
- Maximum concentration (Cmax) of dabrafenib dose(s) [ 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. ]To calculate the dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents), the Cmax of dabrafenib that achieves similar exposure to the dabrafenib adult dose will be evaluated.
- Area under the concentration-time curve over the dosing interval (AUC(0-τ)) and AUC from zero to infinity (AUC(0-inf)) of dabrafenib dose(s) [ 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. ]To calculate the dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents) the AUC(0-τ) and AUC(0-inf) of dabrafenib that achieves similar exposure to the dabrafenib adult dose will be evaluated.
- Pre-dose (trough) concentration (C tau) of dabrafenib and its metabolites [ Time Frame: Day 1-Predose, Day 15-Predose ]Pharmacokinetic data will include C trough of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
- The AUC(0-t) and AUC(0-tau) of dabrafenib and its metabolites [ 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. ]Pharmacokinetic data will include area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]), AUC(0-tau) of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
- Apparent clearance following oral dosing (CL/F) of dabrafenib [ 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. ]Pharmacokinetic data will include CL/F of dabrafenib.
- Cmax of dabrafenib, and its metabolites [ 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. ]Pharmacokinetic data will include Cmax of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
- Time from administration to Cmax (tmax) of dabrafenib and its metabolites [ 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. ]Pharmacokinetic data will include tmax of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
- Elimination half life (t½) of dabrafenib and its metabolites [ 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. ]Pharmacokinetic data will include t½ of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
- Incidence of treatment emergent Adverse Events (safety and tolerability) [ Time Frame: Up to 6 months ]The distribution of adverse events will be 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 tumor response of dabrafenib [ Time Frame: Up to 6 months ]Anti-tumor activity will be assessed based on clinical evidence and the response evaluation criteria in solid tumors (RECIST) version 1.1 criteria for solid tumors, response assessment in neuro-oncology (RANO) criteria (glioma subjects) and langerhans cell histiocytosis (LCH) scoring system.
- Effect of age and weight on CL/F of dabrafenib [ 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. ]The CL/F data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
- Effect of age and weight on volume of distribution (V/F) of dabrafenib [ 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. ]The V/F data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
- Effect of age and weight on absorption rate (ka) of dabrafenib [ 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. ]The ka data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
- Effect of age and weight on coefficients for significant covariates of dabrafenib [ 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. ]The coefficients for significant covariates data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.

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Ages Eligible for Study: | 12 Months to 17 Years (Child) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01677741
United States, Arizona | |
Novartis Investigative Site | |
Phoenix, Arizona, United States, 85016-7710 | |
United States, California | |
Novartis Investigative Site | |
Orange, California, United States, 92868 | |
United States, Maryland | |
Novartis Investigative Site | |
Baltimore, Maryland, United States, 21287 | |
United States, Massachusetts | |
Novartis Investigative Site | |
Boston, Massachusetts, United States, 02215 | |
United States, New York | |
Novartis Investigative Site | |
New York, New York, United States, 10065 | |
United States, Ohio | |
Novartis Investigative Site | |
Cincinnati, Ohio, United States, 45229 | |
United States, Tennessee | |
Novartis Investigative Site | |
Memphis, Tennessee, United States, 38105-3678 | |
United States, Washington | |
Novartis Investigative Site | |
Seattle, Washington, United States, 98105 | |
Australia, Victoria | |
Novartis Investigative Site | |
Parkville, Victoria, Australia, 3052 | |
Canada, Ontario | |
Novartis Investigative Site | |
Toronto, Ontario, Canada, M5G 1X8 | |
Denmark | |
Novartis Investigative Site | |
Copenhagen, Denmark, DK-2100 | |
France | |
Novartis Investigative Site | |
Marseille Cedex 5, France, 13385 | |
Novartis Investigative Site | |
Paris cedex 05, France, 75248 | |
Novartis Investigative Site | |
Paris cedex 12, France, 75571 | |
Novartis Investigative Site | |
Toulouse cedex 9, France, 31059 | |
Novartis Investigative Site | |
Villejuif Cedex, France, 94805 | |
Germany | |
Novartis Investigative Site | |
Heidelberg, Baden-Wuerttemberg, Germany, 69120 | |
Novartis Investigative Site | |
Regensburg, Bayern, Germany, 93053 | |
Novartis Investigative Site | |
Berlin, Germany, 13353 | |
Israel | |
Novartis Investigative Site | |
Jerusalem, Israel, 91120 | |
Novartis Investigative Site | |
Ramat-Gan, Israel, 52621 | |
Italy | |
Novartis Investigative Site | |
Milan, Italy, 20133 | |
Spain | |
Novartis Investigative Site | |
Esplugues De Llobregat. Barcelona, Spain, 08950 | |
Novartis Investigative Site | |
Madrid, Spain, 28009 | |
United Kingdom | |
Novartis Investigative Site | |
Sutton, Surrey, United Kingdom, SM2 5PT | |
Novartis Investigative Site | |
London, United Kingdom, WC1N 3JH |
Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
Responsible Party: | Novartis Pharmaceuticals |
ClinicalTrials.gov Identifier: | NCT01677741 |
Other Study ID Numbers: |
116013 2012-001499-12 ( EudraCT Number ) CDRB436A2102 ( Other Identifier: Novartis ) |
First Posted: | September 3, 2012 Key Record Dates |
Last Update Posted: | March 4, 2021 |
Last Verified: | February 2021 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Children and Adolescents BRAF dabrafenib dose escalation |
BRF116013 V600-mutation positive BRF |
Brain Neoplasms Central Nervous System Neoplasms Nervous System Neoplasms Neoplasms by Site Neoplasms Brain Diseases Central Nervous System Diseases |
Nervous System Diseases Dabrafenib Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |