Study of efficacy and safety of dabrafenib in combination with trametinib in pediatric patients with BRAF V600 mutation positive relapsed or refractory HGG tumors
- Conditions
- Paediatric patients with BRAF V600 mutation positive relapsed or refractory High Grade Glioma (HGG)MedDRA version: 20.0 Level: PT Classification code 10065443 Term: Malignant glioma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2015-004015-20-FR
- Lead Sponsor
- ovartis Pharma AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- Not specified
- Target Recruitment
- 40
Key
- Male or female between = 6 and <18 years of age at the time of signing the informed
consent form
- Relapsed, progressed, or failed to respond to frontline therapy. Frontline therapy is
presumed to be optimal surgical approach (biopsy or resection) with radiation and/or
chemotherapy.
- Histologically confirmed diagnosis of High Grade Glioma (Grade III or IV glioma as
defined by WHO histological classification system, revised 2016, see Appendix 4),
including anaplastic pleomorphic xanthoastrocytoma (aPXA) and anaplastic
gangliogliomas.
- Locally determined and centrally confirmed measurable disease with minimal biperpendicular diameter that must be at least twice the imaging slice thickness to be used for efficacy assessments. (Both local and centrally confirmed results must show
measurable disease to meet eligibility)
- BRAF V600 mutation-positive tumor as locally determined using molecular methods in a
CLIA-approved laboratory or equivalent, or at a Novartis designated central reference
laboratory upon request
- Tumor tissue (newly obtained or archival paraffin blocks/slides) must be available and
subsequently provided to Novartis for central confirmatory testing of HGG histopathology
and BRAF mutational status.
- Performance score of =50% according to the Karnofsky/Lansky performance status scale
- Females of child-bearing potential must be willing to practice acceptable methods of birth control. Additionally, females of childbearing potential must have a negative serum
pregnancy test within 7 days prior to day 1
- Must have adequate bone marrow function in the absence of growth factor support and is defined as:
? -Absolute neutrophil count (ANC) =1000/µL;
? -Platelets =75,000/µL and transfusion independent, defined as not receiving platelet
transfusions within a 7 day period prior to meeting this enrollment criteria
? -Hemoglobin =8.0 g/dL (may receive red blood cell transfusions)
- Adequate renal function defined as:
? -Calculated eGFR (Schwartz formula, http://www.medcalc /pedigfr.html), or
radioisotope GFR =90 mL/min/1.73 m2; or
? -A serum creatinine within the testing lab reference range (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
? -AST and ALT =2.5 x ULN
- Adequate cardiac function defined as:
? -LVEF greater than or equal to institutional LLN by ECHO (while not receiving
medications for cardiac function)
? -Corrected QT (QTcF) interval =480 msecs.
- Able to swallow capsules:
? -If less than 12 years old, must be = 16kg body weight
? -If = 12 years old, must be = 19kg body weight
- If receiving glucocorticoids, patient must be on a stable or weaning dose for at least 7 days prior to the f
- Malignancy OTHER than BRAF V600 mutant HGG.
- Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK
inhibitor, or ERK inhibitor.
- Cancer therapy (chemotherapy with delayed toxicity, immunotherapy, biologic therapy,
vaccine therapy) or investigational drugs within 3 weeks preceding the first dose of study
treatment.
- Radiotherapy to CNS glioma lesions within 3 months prior to first dose of study treatment, unless there is clear evidence of radiologic progression outside of the field of radiation.
- History of malignancy with confirmed activating RAS mutation or with BRAF fusion
such as BRF-KIAA1549. Note: Prospective RAS testing is not required. However, if the
results of previous RAS testing are known, they must be used in assessing eligibility.
- Current use of a prohibited medication or herbal preparation or requires any of these
medications during the study. See Section 6.4 for details.
- Unresolved toxicity greater than NCI CTCAE v 4.03 grade 2 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 the study treatment (e.g.,
alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based
chemotherapy).
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to dabrafenib, trametinib and their excipients.
- Autologous or allogeneic stem cell transplant within 3 months prior to the first dose of
study treatment
- History or current diagnosis of cardiac disease indicating significant risk of safety for
patients participating in the study such as uncontrolled or significant cardiac disease,
including any of the following:
? recent myocardial infarction (within last 6 months),
? uncontrolled congestive heart failure,
? unstable angina (within last 6 months),
? clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g.,
sustained ventricular tachycardia, and clinically significant second or third degree AV
block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to
the first dose of study treatment
? coronary angioplasty or stenting (within last 6 months)
? intra-cardiac defibrillators
? abnormal cardiac valve morphology (=grade 2) documented by echocardiogram
(patients with grade 1 abnormalities can be enrolled on study. Patients with moderate valvular thickening should NOT be enrolled)
- 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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method