BRF116013: A Phase I/IIa, 2 Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib in Pediatric Patients Aged 1 Month to <18 years with Advanced BRAF V600-Mutation Positive Solid Tumors.

Why are we doing this research?


This is a 2-part, study to determine the safety, tolerability and pharmacokinetics of oral dabrafenib in pediatric 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 4.5 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 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. 

Study Type:  Interventional
Masking: Open Label
Primary Purpose: Treatment 

Who can participate?

AGES ELIGIBLE FOR STUDY:  1 Month to 17 Years


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 between one month and <18 years of age (inclusive) at the time of signing the informed consent form
  • Recurrent disease or progressive disease after having received at least one standard therapy for their disease
  • At least one evaluable lesion
  • BRAF V600 mutation-positive tumor as confirmed in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory or equivalent
  • 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) and males with reproductive potential must be willing to practice acceptable methods of birth control.
  • 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 creatinine clearance (Cockcroft-Gault), calculated glomerular filtration rate (GFR) (revised Schwartz formula), or radioisotope GFR >=60 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 liver metastases are present (requires radiographic confirmation of liver metastases) and 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, or (e) indolent prostate cancer (definition: clinical stage T1 or T2a, Gleason score <=6, and prostate specific antigen [PSA] <10 nanograms (ng)/mL) requiring no or only anti-hormonal therapy with histologically confirmed tumour lesions that can be clearly differentiated from lung cancer target and non-target lesions 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 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
  • 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, moderate valvular thickening. Subjects with known glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • 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.
  • A history of known Human Immunodeficiency Virus (HIV), 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 and lactating females who are actively breast feeding.


  • Cancer - Kidney Tumors
  • Cancer - Liver Tumors
  • Cancer - Neuroblastoma
  • Cancer - Neurofibromatosis Tumors
  • Cancer - Retinoblastoma


  • Female
  • Male


For more information contact:

Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039

Phone: 513-636-2799