A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects
Basic Trial Information
|Phase I||Biomarker/Laboratory analysis, Treatment||Active||1 month to 17 years||116013|
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.
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
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).
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
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
Johns Hopkins University/Sidney Kimmel Cancer Center
Kenneth J. Cohen
Boston Children's Hospital
Mark William Kieran
Dana-Farber Cancer Institute
Mark William Kieran
Memorial Sloan-Kettering Cancer Center
Christine Anne Pratilas
St. Jude Children's Research Hospital
Fred Hutch/University of Washington Cancer Consortium
Sarah E. Sherr Leary
Link to the current ClinicalTrials.gov record.
NLM Identifier 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.