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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01677741




Registration number
NCT01677741
Ethics application status
Date submitted
30/08/2012
Date registered
3/09/2012
Date last updated
9/06/2020

Titles & IDs
Public title
A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects
Scientific 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
Secondary ID [1] 0 0
2012-001499-12
Secondary ID [2] 0 0
116013
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms, Brain 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Dabrafenib

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.

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.

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.

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.

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.


Treatment: Drugs: 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.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by number of subjects with adverse events (AEs) - Safety and tolerability parameters will include recording of AEs, in Part 1 and Part 2 of the study.
Timepoint [1] 0 0
Up to 6 months
Primary outcome [2] 0 0
Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in ECG readings - Safety and tolerability parameters will include the electrocardiogram (ECG) readings at Baseline and at end of Part 1 and Part 2 of the study.
Timepoint [2] 0 0
Up to 6 months
Primary outcome [3] 0 0
Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in ECHO findings - Safety and tolerability parameters will include recording of echocardiogram (ECHO) at Baseline and at end of Part 1 and Part 2 of the study.
Timepoint [3] 0 0
Up to 6 months
Primary outcome [4] 0 0
Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in laboratory values - Safety and tolerability parameters will include laboratory values at Baseline and at end of Part 1 and Part 2 of the study.
Timepoint [4] 0 0
Up to 6 months
Primary outcome [5] 0 0
Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in vital signs - Safety and tolerability parameters will include vital signs at Baseline and at end of Part 1 and Part 2 of the study.
Timepoint [5] 0 0
Up to 6 months
Primary outcome [6] 0 0
Maximum concentration (Cmax) of dabrafenib dose(s) - 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.
Timepoint [6] 0 0
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.
Primary outcome [7] 0 0
Area under the concentration-time curve over the dosing interval (AUC(0-t)) and AUC from zero to infinity (AUC(0-inf)) of dabrafenib dose(s) - To calculate the dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents) the AUC(0-t) and AUC(0-inf) of dabrafenib that achieves similar exposure to the dabrafenib adult dose will be evaluated.
Timepoint [7] 0 0
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.
Secondary outcome [1] 0 0
Pre-dose (trough) concentration (C tau) of dabrafenib and its metabolites - Pharmacokinetic data will include C trough of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Timepoint [1] 0 0
Day 1-Predose, Day 15-Predose
Secondary outcome [2] 0 0
The AUC(0-t) and AUC(0-tau) of dabrafenib and its metabolites - 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]).
Timepoint [2] 0 0
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.
Secondary outcome [3] 0 0
Apparent clearance following oral dosing (CL/F) of dabrafenib - Pharmacokinetic data will include CL/F of dabrafenib.
Timepoint [3] 0 0
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.
Secondary outcome [4] 0 0
Cmax of dabrafenib, and its metabolites - Pharmacokinetic data will include Cmax of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Timepoint [4] 0 0
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.
Secondary outcome [5] 0 0
Time from administration to Cmax (tmax) of dabrafenib and its metabolites - Pharmacokinetic data will include tmax of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Timepoint [5] 0 0
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.
Secondary outcome [6] 0 0
Elimination half life (t½) of dabrafenib and its metabolites - Pharmacokinetic data will include t½ of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Timepoint [6] 0 0
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.
Secondary outcome [7] 0 0
Longer term safety and tolerability of dabrafenib as assessed by number of subjects with AEs - Safety and tolerability parameters will include recording of AEs, in Part 1 and Part 2 of the study.
Timepoint [7] 0 0
Up to 6 months
Secondary outcome [8] 0 0
Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in ECG readings - Safety and tolerability parameters will include the electrocardiogram (ECG) readings at Baseline and at end of Part 1 and Part 2 of the study
Timepoint [8] 0 0
Up to 6 months
Secondary outcome [9] 0 0
Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in laboratory values - Safety and tolerability parameters will include laboratory values at Baseline and at end of Part 1 and Part 2 of the study.
Timepoint [9] 0 0
Up to 6 months
Secondary outcome [10] 0 0
Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in vital signs - Safety and tolerability parameters will include vital signs at Baseline and at end of Part 1 and Part 2 of the study.
Timepoint [10] 0 0
Up to 6 months
Secondary outcome [11] 0 0
Overall tumor response of dabrafenib - 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.
Timepoint [11] 0 0
Up to 6 months
Secondary outcome [12] 0 0
Effect of age and weight on CL/F of dabrafenib - The CL/F data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
Timepoint [12] 0 0
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.
Secondary outcome [13] 0 0
Effect of age and weight on volume of distribution (V/F) of dabrafenib - The V/F data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
Timepoint [13] 0 0
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.
Secondary outcome [14] 0 0
Effect of age and weight on absorption rate (ka) of dabrafenib - The ka data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
Timepoint [14] 0 0
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.
Secondary outcome [15] 0 0
Effect of age and weight on coefficients for significant covariates of dabrafenib - The coefficients for significant covariates data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
Timepoint [15] 0 0
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.

Eligibility
Key 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).
Minimum age
12 Months
Maximum age
17 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Parkville
Recruitment postcode(s) [1] 0 0
3052 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
New York
Country [6] 0 0
United States of America
State/province [6] 0 0
Ohio
Country [7] 0 0
United States of America
State/province [7] 0 0
Tennessee
Country [8] 0 0
United States of America
State/province [8] 0 0
Washington
Country [9] 0 0
Canada
State/province [9] 0 0
Ontario
Country [10] 0 0
Denmark
State/province [10] 0 0
Copenhagen
Country [11] 0 0
France
State/province [11] 0 0
Marseille Cedex 5
Country [12] 0 0
France
State/province [12] 0 0
Paris cedex 05
Country [13] 0 0
France
State/province [13] 0 0
Paris cedex 12
Country [14] 0 0
France
State/province [14] 0 0
Toulouse cedex 9
Country [15] 0 0
France
State/province [15] 0 0
Villejuif Cedex
Country [16] 0 0
Germany
State/province [16] 0 0
Baden-Wuerttemberg
Country [17] 0 0
Germany
State/province [17] 0 0
Bayern
Country [18] 0 0
Germany
State/province [18] 0 0
Berlin
Country [19] 0 0
Israel
State/province [19] 0 0
Jerusalem
Country [20] 0 0
Israel
State/province [20] 0 0
Ramat-Gan
Country [21] 0 0
Italy
State/province [21] 0 0
Milan
Country [22] 0 0
Spain
State/province [22] 0 0
Esplugues De Llobregat. Barcelona
Country [23] 0 0
Spain
State/province [23] 0 0
Madrid
Country [24] 0 0
United Kingdom
State/province [24] 0 0
Surrey
Country [25] 0 0
United Kingdom
State/province [25] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a 2-part, study to determine the safety, tolerability and pharmacokinetics of oral
dabrafenib in children and adolescent subjects with advanced BRAF V600 mutation-positive
solid tumors. Part 1 (dose escalation study) will identify the recommended Part 2
(tumor-specific expansion study) dose and regimen using a dose-escalation procedure.
Approximately 6 to 18 subjects will participate in Part 1 and will receive a starting dose of
3 mg/kg and dose will deescalate or escalate between 1.5 milligram (mg)/kilogram (kg) and 6
mg/kg. Up to 6 subjects will be enrolled at one dose level dependent upon the number of
subjects at the current dose level, the number of subjects who have experienced a dose
limiting toxicity (DLT) at the current dose level, and the number of subjects enrolled but
with data pending at the current dose level. Escalation may proceed until either a maximum
tolerated dose (MTD) is established, or until the dose in which the median pharmacokinetic
parameters consistent with exposure in adults are achieved. Cohorts may be added in order to
evaluate additional dose levels. Part 2 consists of four disease-specific cohorts of subjects
with tumors known to have BRAF V600 activation (pediatric low-grade gliomas, pediatric
high-grade gliomas, Langerhans cell histiocytosis [LCH], and other tumors such as melanoma
and papillary thyroid carcinoma [PTC]). Each cohort will enroll at least 10 subjects with a
pre-dose and at least 1 post-dose disease assessment. In both the parts of the study, on Day
1, a single first dose will be administered, and repeat dosing will begin on Day 2. PK
sampling will be performed on Day 1 and Day 15 for subjects >=25 kg in weight. For subjects
<25 kg and >=10 kg in weight, blood samples for PK analysis will be collected on Day 1 and
Day 15. For subjects <10kg in weight, blood samples for PK analysis will be collected after
repeated administration on Day 15 only. Safety and tolerability will be assessed throughout
the study. Treatment with dabrafenib will be continued until disease progression or until no
clinical benefit or development of an unacceptable toxicity, or until they withdraw consent
or begin a new therapy. At the end of treatment, a final study visit will occur.
Trial website
https://clinicaltrials.gov/show/NCT01677741
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications