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

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Basic Trial Information

PhaseTypeStatusAgeTrial IDs
Phase IBiomarker/Laboratory analysis, TreatmentActive1 month to 17 years116013
NCI-2013-00631, NCT01677741

Trial Description


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.

Eligibility Criteria

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


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


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.

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Novartis Pharmaceuticals Corporation

    Trial Sites



    Johns Hopkins University/Sidney Kimmel Cancer Center

    Kenneth J. Cohen
    Principal Investigator


    Boston Children's Hospital

    Mark William Kieran
    Principal Investigator

    Dana-Farber Cancer Institute

    Mark William Kieran
    Principal Investigator

    New York
    New York

    Memorial Sloan-Kettering Cancer Center

    Christine Anne Pratilas
    Principal Investigator


    St. Jude Children's Research Hospital

    Alberto Broniscer
    Principal Investigator


    Fred Hutch/University of Washington Cancer Consortium

    Sarah E. Sherr Leary
    Principal Investigator

    Link to the current record.
    NLM Identifier NCT01677741

    Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the record via the link above for more information about participating sites.