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

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IBiomarker/Laboratory analysis, Treatment1 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:

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).

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 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).

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).

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 .

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).

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).

At least one evaluable lesion.

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.

Male or female >=12 months and <18 years of age at the time of signing the informed

consent form.

Written informed consent - a signed informed consent and/or assent (as age

appropriate) will be obtained according to institutional guidelines.

Exclusion Criteria:

Lactating females who are actively breast feeding.

Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at

screening or prior to dosing.

Hepatitis B Virus, or Hepatitis C Virus infection (subjects with laboratory evidence

of Hepatitis B Virus clearance may be enrolled).

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.

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.

Known, uncontrolled cardiac arrhythmias (except sinus arrhythmia) within the past 24


Subjects with moderate valvular thickening.

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).

History of myocardial infarction, severe or unstable angina, peripheral vascular

disease or familial QTc prolongation.

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 allergic reactions attributed to compounds of similar chemical or biologic

composition to dabrafenib and its excipients.

Has leukaemia.

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).

Current use of a prohibited medication or herbal preparation or requires any of these

medications during the study.

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.

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).

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.

Malignancy OTHER than the BRAF mutant malignancy under study.

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).

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators


    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

    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 Hutchinson Cancer Research Center/University of Washington Cancer Consortium

    Sarah E. Sherr Leary
    Principal Investigator

    Link to the current ClinicalTrials.gov record.
    NLM Identifer NCT01677741

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