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

Status: Recruiting
DFCI Protocol ID: 12-429

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.

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Mark Kieran, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:


Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

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 .

  -  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).

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.

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