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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01677741




Registration number
NCT01677741
Ethics application status
Date submitted
30/08/2012
Date registered
3/09/2012
Date last updated
24/11/2021

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
Incidence of Treatment Emergent Adverse Events (AEs) in Part 1 (Dose Escalation)
Timepoint [1] 0 0
From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
Primary outcome [2] 0 0
Maximum Concentration (Cmax) of Dabrafenib
Timepoint [2] 0 0
Week 1 Day 1, Week 3 Day 15
Primary outcome [3] 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
Timepoint [3] 0 0
Week 1 Day 1
Secondary outcome [1] 0 0
Pre-dose (Trough) Concentration (C Tau) of Dabrafenib and Its Metabolites
Timepoint [1] 0 0
Week 3 Day 15
Secondary outcome [2] 0 0
The AUC(0-t) of Dabrafenib Metabolites
Timepoint [2] 0 0
Week 1 Day 1, Week 3 Day 15
Secondary outcome [3] 0 0
The AUC(0-tau) of Dabrafenib and Its Metabolites
Timepoint [3] 0 0
Week 1 Day 1, Week 3 Day 15
Secondary outcome [4] 0 0
Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Dabrafenib
Timepoint [4] 0 0
Week 1 Day 1, Week 3 Day 15
Secondary outcome [5] 0 0
Maximum Concentration (Cmax) of Dabrafenib Metabolites
Timepoint [5] 0 0
Week 1 Day 1, Week 3 Day 15
Secondary outcome [6] 0 0
Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax) of Dabrafenib and Its Metabolites
Timepoint [6] 0 0
Week 1 Day 1, Week 3 Day 15
Secondary outcome [7] 0 0
Elimination Half Life (T½) of Dabrafenib and Its Metabolites
Timepoint [7] 0 0
Week 3 Day 15
Secondary outcome [8] 0 0
Incidence of Treatment Emergent Adverse Events (AEs) in Part 2 (Tumor Specific Expansion)
Timepoint [8] 0 0
From study treatment start date till 28 days safety follow-up, assessed up to approximately 90 months
Secondary outcome [9] 0 0
Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for Low Grade Glioma (LLG) Subjects
Timepoint [9] 0 0
Up to 6 months
Secondary outcome [10] 0 0
Best Overall Response Based on Investigator Assessment Per Response Assessment in Neuro-Oncology (RANO) Criteria for High Grade Glioma (HGG) Subjects
Timepoint [10] 0 0
Up to 6 months
Secondary outcome [11] 0 0
Effect of Weight on Total Apparent Clearance (CL/F) of Dabrafenib Estimated With a PopPK Model
Timepoint [11] 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 [12] 0 0
Effect of Weight on Volume of Distribution (V/F) of Dabrafenib Estimated With a PopPK Model
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 Weight on Absorption Rate (ka) of Dabrafenib Estimated With a PopPK Model
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 Weight on Coefficients for Significant Covariates of Dabrafenib Estimated With a PopPK Model
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.

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
Sex
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
Parallel
Other design features
Phase
Phase 1/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
23/05/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
4/12/2020
Sample size
Target
Accrual to date
Final
85
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 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.
Trial website
https://clinicaltrials.gov/ct2/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