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

NCT01677741

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.

Related Conditions:
  • Glioma
  • Langerhans Cell Histiocytosis
  • Malignant Solid Tumor
  • Melanoma
  • Thyroid Gland Papillary Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study to Determine Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib In Children and Adolescent Subjects
  • Official Title: Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of Oral Dabrafenib in Children and Adolescent Subjects With Advanced BRAF V600-Mutation Positive Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 116013
  • NCT ID: NCT01677741

Conditions

  • Neoplasms, Brain

Interventions

DrugSynonymsArms
DabrafenibPart 2: Cohort 1 Low-Grade Gliomas with BRAF V600 mutations

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part 1: Dabrafenib treatmentExperimentalThree subjects will receive a single dose of 3 mg/kg dabrafenib on Day 1 and repeat dose will begin from Day 2, evenly divided in two daily doses. Once all 3 subjects have been fully evaluated for the first 28 days (including Day 15 PK) and no DLTs are observed, a next subject will be enrolled at the next higher dose levels (i.e., dose escalation to 3.75 mg/kg [+1] and may be further to 4.5 mg/kg [+2] and so on). If all 3 subjects have not been fully evaluated for the first 28 days or 1 DLT occurred, the fourth subject will be enrolled at the same dose level. If 2 or more DLTs are observed, the next subject will be enrolled at the next lower dose level (i.e., de-escalated to 2.25 mg/kg [-1] and may be further to 1.5 mg/kg [-2]). Similarly, the process is repeated for the fifth and sixth subjects in a cohort. All subjects will receive treatment till end of study.
  • Dabrafenib
Part 2: Cohort 1 Low-Grade Gliomas with BRAF V600 mutationsExperimentalSubjects with low-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.
  • Dabrafenib
Part 2: Cohort 2 High-Grade Gliomas with BRAF V600 mutationsExperimentalSubjects with high-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.
  • Dabrafenib
Part 2: Cohort 3 LCH with BRAF V600 mutationsExperimentalSubjects with LCH with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.
  • Dabrafenib
Part 2: Cohort 4 Melanoma and PTC with BRAF V600 mutationsExperimentalSubjects with other tumors with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.
  • Dabrafenib

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
             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
             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.

          -  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.
      
Maximum Eligible Age:17 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by number of subjects with adverse events (AEs)
Time Frame:Up to 6 months
Safety Issue:
Description:Safety and tolerability parameters will include recording of AEs, in Part 1 and Part 2 of the study.

Secondary Outcome Measures

Measure:Pre-dose (trough) concentration (C tau) of dabrafenib and its metabolites
Time Frame:Day 1-Predose, Day 15-Predose
Safety Issue:
Description:Pharmacokinetic data will include C trough of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Measure:The AUC(0-t) and AUC(0-tau) of dabrafenib and its metabolites
Time Frame:Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Safety Issue:
Description:Pharmacokinetic data will include area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]), AUC(0-tau) of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Measure:Apparent clearance following oral dosing (CL/F) of dabrafenib
Time Frame:Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Safety Issue:
Description:Pharmacokinetic data will include CL/F of dabrafenib.
Measure:Cmax of dabrafenib, and its metabolites
Time Frame:Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Safety Issue:
Description:Pharmacokinetic data will include Cmax of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Measure:Time from administration to Cmax (tmax) of dabrafenib and its metabolites
Time Frame:Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Safety Issue:
Description:Pharmacokinetic data will include tmax of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Measure:Elimination half life (t½) of dabrafenib and its metabolites
Time Frame:Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Safety Issue:
Description:Pharmacokinetic data will include t½ of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
Measure:Longer term safety and tolerability of dabrafenib as assessed by number of subjects with AEs
Time Frame:Up to 6 months
Safety Issue:
Description:Safety and tolerability parameters will include recording of AEs, in Part 1 and Part 2 of the study.
Measure:Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in ECG readings
Time Frame:Up to 6 months
Safety Issue:
Description:Safety and tolerability parameters will include the electrocardiogram (ECG) readings at Baseline and at end of Part 1 and Part 2 of the study
Measure:Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in laboratory values
Time Frame:Up to 6 months
Safety Issue:
Description:Safety and tolerability parameters will include laboratory values at Baseline and at end of Part 1 and Part 2 of the study.
Measure:Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in vital signs
Time Frame:Up to 6 months
Safety Issue:
Description:Safety and tolerability parameters will include vital signs at Baseline and at end of Part 1 and Part 2 of the study.
Measure:Overall tumor response of dabrafenib
Time Frame:Up to 6 months
Safety Issue:
Description:Anti-tumor activity will be assessed based on clinical evidence and the response evaluation criteria in solid tumors (RECIST) version 1.1 criteria for solid tumors, response assessment in neuro-oncology (RANO) criteria (glioma subjects) and langerhans cell histiocytosis (LCH) scoring system.
Measure:Effect of age and weight on CL/F of dabrafenib
Time Frame:Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Safety Issue:
Description:The CL/F data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
Measure:Effect of age and weight on volume of distribution (V/F) of dabrafenib
Time Frame:Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Safety Issue:
Description:The V/F data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
Measure:Effect of age and weight on absorption rate (ka) of dabrafenib
Time Frame:Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Safety Issue:
Description:The ka data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
Measure:Effect of age and weight on coefficients for significant covariates of dabrafenib
Time Frame:Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
Safety Issue:
Description:The coefficients for significant covariates data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • Children and Adolescents
  • BRAF
  • dabrafenib
  • dose escalation
  • BRF116013
  • V600-mutation positive
  • BRF

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