Last updated: 11/03/2018 18:51:30
This product has been transferred to Novartis. GSK Clinical Study Register is no longer maintained for this study. The most up to date information is available on clinicaltrials.gov.
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
GSK study ID
116013
Clinicaltrials.gov ID
EudraCT ID
EU CT Number
Not applicable
Trial status
No longer a GSK study
No longer a GSK study
Trial overview
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
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.
Primary purpose:
Treatment
Trial design:
Single Group Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:
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)
Timeframe: Up to 6 months
Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in ECG readings
Timeframe: Up to 6 months
Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in ECHO findings
Timeframe: Up to 6 months
Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in laboratory values
Timeframe: Up to 6 months
Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in vital signs
Timeframe: Up to 6 months
Maximum concentration (Cmax) of dabrafenib dose(s)
Timeframe: 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.
Area under the concentration-time curve over the dosing interval (AUC(0-τ)) and AUC from zero to infinity (AUC(0-inf)) of dabrafenib dose(s)
Timeframe: 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.
Secondary outcomes:
Pre-dose (trough) concentration (C tau) of dabrafenib and its metabolites
Timeframe: Day 1-Predose, Day 15-Predose
The AUC(0-t) and AUC(0-tau) of dabrafenib and its metabolites
Timeframe: 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.
Apparent clearance following oral dosing (CL/F) of dabrafenib
Timeframe: 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.
Cmax of dabrafenib, and its metabolites
Timeframe: 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.
Time from administration to Cmax (tmax) of dabrafenib and its metabolites
Timeframe: 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.
Elimination half life (t½) of dabrafenib and its metabolites
Timeframe: 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.
Longer term safety and tolerability of dabrafenib as assessed by number of subjects with AEs
Timeframe: Up to 6 months
Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in ECG readings
Timeframe: Up to 6 months
Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in laboratory values
Timeframe: Up to 6 months
Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in vital signs
Timeframe: Up to 6 months
Overall tumor response of dabrafenib
Timeframe: Up to 6 months
Effect of age and weight on CL/F of dabrafenib
Timeframe: 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.
Effect of age and weight on volume of distribution (V/F) of dabrafenib
Timeframe: 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.
Effect of age and weight on absorption rate (ka) of dabrafenib
Timeframe: 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.
Effect of age and weight on coefficients for significant covariates of dabrafenib
Timeframe: 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.
Interventions:
Enrollment:
86
Primary completion date:
Not applicable
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Not applicable
Medical condition
Neoplasms, Brain
Product
dabrafenib
Collaborators
None
Study date(s)
February 2013 to October 2016
Type
Interventional
Phase
1
Participation criteria
Sex
Female & Male
Age
12 Months - 17 Years
Accepts healthy volunteers
none
- 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.
- 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.
Inclusion and exclusion 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.
Trial location(s)
This study does not involve prospective enrollment of participants.
Study documents
No study documents available.
Results overview
Study Results yet to be posted
Recruitment status
No longer a GSK study
Actual primary completion date
Not applicable
Actual study completion date
Not applicable
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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